Methods for treating hepatitis c

ABSTRACT

In accordance with the present invention, compounds that inhibit viral replication, preferably Hepatitis C Virus (HCV) replication, have been identified, and methods for their use provided. In one aspect of the invention, compounds useful in the treatment or prevention of a viral infection are provided. In another aspect of the invention, compounds useful in the treatment or prevention of HCV infection are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No. 11/180,961, filed on Jul. 14, 2005, which claims the benefit of each of U.S. Provisional Application No. 60/587,487, filed Jul. 14, 2004, U.S. Provisional Application No. 60/634,979, filed Dec. 13, 2004, U.S. Provisional Application No. 60/645,586, filed Jan. 24, 2005, U.S. Provisional Application No. 60/665,349, filed Mar. 28, 2005, and U.S. Provisional Application No. 60/675,440, filed Apr. 28, 2005, all of which applications are incorporated herein by reference in their entireties. This application corresponds to International Application PCT/US2005/024881, filed Jul. 14, 2005, which application is herein incorporated by reference in its entirety.

GOVERNMENT SUPPORT

The present invention was made with U.S. Government support under DHHS Grant No. 5R44 AI054029-03. The U.S. Government has certain rights in the invention.

FIELD OF THE INVENTION

The present invention relates to methods for treating Hepatitis C using Indole compounds that modify translational control of Hepatitis C virus.

BACKGROUND OF THE INVENTION

An estimated 170 million people worldwide are reported to be infected with hepatitis C virus (HCV), the causative agent of hepatitis C. Seventy to eighty percent of HCV infections lead to chronic liver infection, which in turn may result in sever liver disease, including liver fibrosis, cirrhosis, and hepatocellular carcinoma (115).

HCV constitutes the Hepacivirus genus of the family Flaviviridae (106), and contains a positive-stranded 9.6 kb RNA genome. The features of the HCV genome include a 5′-untranslated region (UTR) that encodes an internal ribosome entry site (IRES) that directs the translation of a single long open reading frame (ORF) encoding a polyprotein of 3,010 amino acids. The HCV ORF is followed by a 3′-UTR of variable length, depending on the HCV variant, that encodes the sequences required for the initiation of antigenomic strand synthesis (79).

The HCV IRES and 3′-UTR both encode regions of RNA structures that are required for genome translation and replication. The HCV polyprotein is posttranslationally processed into at least 10 mature viral proteins, including the structural proteins core (putative nucleocapsid), E1 and E2 and the nonstructural (NS) proteins NS2 to NS5B.

Three distinct elements have been shown to be involved in HCV IRES-mediated translation: (1) integrity of the global structure of HCV IRES, (2) the 3′-terminal region of the HCV genome; and (3) trans-acting cellular factors that interact with the HCV IRES element and assist in translation initiation (35).

The initiation of protein synthesis in eukaryotic cells predominantly follows the 5′ cap-dependent, first AUG rule (61). However, an increasing number of viral (6, 12, 28, 31a, 50, 95, 97, 98, 105, 128) and cellular mRNAs (18, 39, 45, 78, 91, 130) have been shown to use an IRES element to direct translation initiation. In 1992, an IRES element was reported in the 5′ UTR of the HCV RNA genome (129), indicating that synthesis of the viral protein is initiated in a cap-independent fashion.

A bicistronic expression system can be used to define and evaluate the function of IRES elements. This test system harbors two different reporter genes in which the 5′-proximal reporter gene is expressed by a cap dependent translation mechanism while the second reporter is expressed only if an upstream sequence inserted in the intergenic space contains an IRES sequence element. Using this system, a putative IRES in the HCV 5′ UTR was unambiguously demonstrated to function as an IRES involved in translational control of viral proteins (133). In vitro translation, RNA transfection, and mutagenesis studies provided further evidence that the HCV 5′ UTR contains an IRES element (23, 41, 42, 108, 129, 132, 133, 134). Both in vitro and cell-based studies demonstrated that the HCV IRES guides cellular translation initiation factors to an internal site of the viral RNA (56, 58, 120), thus functionally demonstrating the HCV IRES activity. Taken together, these results demonstrate that the HCV 5′-UTR contains an IRES element that plays an active and crucial role in the mechanism of internal initiation for HCV protein translation.

The IRES is one of the most conserved regions of the HCV genome, reflecting its essential nature for viral replication and protein synthesis (13, 118, 122). Although both 5′ and 3′ sequences of the IRES appear to play a role in the control of initiation of translation (42, 109, 110, 113, 136), the minimal sequence requirement for HCV IRES function has been mapped to a region between nucleotides 44-354 (40).

Biochemical probing and computer modeling indicate that the HCV IRES and its 5′ sequence is folded into a distinct structure that consists of four major domains and a pseudoknot (11, 42, 122). Domain I contains a small stem-loop structure that does not appear to be a functional part of the IRES element while domains II, III, and IV contain the HCV IRES activity (43, 111). The relationships between secondary and tertiary structures of the HCV IRES and their function have recently been established (5, 55, 56, 99, 124). Both domains II and III consist of multiple stems, loops, and bulges and are important for IRES activity (23, 40, 51, 52, 54, 56, 64, 74, 75, 93, 107, 108, 110, 124, 127, 131, 139). Domain II can induce conformational changes on the ribosome that have been implicated in the decoding process (124). Domain III has the highest degree of structural conservation among the different HCV strains. It comprises the core of the flavivirus IRES and has 6 subdomains (40). Various studies have shown that subdomain IIId forms complex secondary/tertiary structures and is critical for initiation activity (55, 56, 57, 124, 129). Domain IV has one stem-loop that spans the initiation codon and is specific for the HCV IRES (41, 122), but the precise role of domain IV in IRES activity remains controversial (41, 112).

The role of the HCV IRES is to position the translational machinery near an internal initiator codon in the viral mRNA. The translation initiation mechanism of the HCV IRES differs significantly from that of 5′-cap-dependent translation initiation (7, 21, 31, 35, 81, 96, 114, 123). Most cellular capped mRNAs utilize a number of initiation factors (eIFs) that are required for the translation initiation process. The initial steps of the process require proteins that interact with the 5′ cap structure and recruit the 40S ribosomal subunit to the cap-proximal region of mRNA. This complex then scans 3′ of the cap, until reaching an AUG codon at which translation will initiate (21, 114). However, in the case of HCV, the IRES functionally replaces the 5′ cap structure, allowing the 40S ribosomal subunit and eIF3 to bind directly to the RNA. Subdomain IIId of the HCV IRES harbors the binding site for the 40S ribosomal subunit and the only initiation factors required for translation initiation are eIF2, eIF3, and eIF4E (15, 58, 94, 100, 120, 124).

The polypyrimidine track-binding protein (PTB) and La autoantigen are noncanonical translation initiation factors that bind to and enhance HCV IRES activity (1, 2, 3, 4, 5, 30, 48, 49, 53). PTB, a 57-kDa protein involved in RNA splicing, is also necessary for efficient IRES-mediated translation initiation of picornavirus mRNA, and some cellular mRNAs (10, 11, 36, 53, 59, 89, 92). The La autoantigen, a 52 kDa double-stranded RNA unwinding protein, also increases the activity of poliovirus and cellular IRESs (38, 85, 86). Other cellular factors involved in HCV IRES-mediated translation initiation include proteasome α-subunit PSMA7 (62), ribosomal protein S5 (26), ribosomal protein S9 (24, 25, 100), and hnRNPL (33). However, the role of these RNA-binding proteins in HCV IRES-mediated initiation of translation is unclear. Recently, it was reported that the activity of interferon (IFN) α against HCV replication might target HCV IRES-mediated translation initiation by causing a reduction of La protein levels (117). Thus, an inhibitor that blocks interaction between the IRES and the noncanonical factors might efficiently inhibit HCV replication and lack cytotoxicity.

Currently, only interferon (IFN) α and the nucleoside analogue ribavirin, in combination, are marketed for the treatment of HCV infection. However, these two agents are immunomodulators and have limited efficacy, relatively high toxicity, and high cost (80, 83, 84, 138). Although the treatment outcome is variable among the six major HCV genotypes, only about one-half of all treated patients respond to therapy, suggesting that the virus encodes protein products that may directly or indirectly attenuate the antiviral action of IFN. IFNs are naturally produced in response to virus infection, and cellular exposure to IFN leads to the induced expression of a variety of IFN-stimulated genes (ISGs), many of which have an antiviral function. ISG action can limit virus replication at multiple points within the replicative cycle.

There remains a need for a more effective means of treating patients afflicted with HCV. Specifically, a need exists for novel antiviral drugs that have no cross-resistance with existing treatment modalities, and which demonstrate synergy with other anti-HCV agents. The applicants set out to identify drug candidates that inhibit HCV infection and were successful in identifying Indole compounds that are useful as anti-HCV agents. Without being limited to one theory, it is believed that the compounds of the present invention inhibit IRES-mediated initiation, elongation, and termination, i.e. translation.

The compounds of the present invention are also useful for inhibiting translation of other cap-independent viruses that contain an IRES element. Such viruses include those of the picornavirus genus, such as poliovirus, hepatitis A virus and rhinovirus; those of the coronavirus genus, such as SARS; those of the arbovirus genus; those of the flavivirus genus, such as yellow fever, dengue, and West Nile virus, herpesviruses, such as herpes simplex virus and Kaposi's sarcoma-associated herpesvirus, or any other virus with a similar mode of replication. Furthermore, compounds of the invention are also useful for inhibiting HIV, or any other virus with a similar mode of translation.

All documents referred to herein are incorporated by reference into the present application as though fully set forth herein.

SUMMARY OF THE INVENTION

In accordance with the present invention, compounds that can inhibit HCV replication have been identified. Also in accordance with the present invention, compounds that can inhibit HCV infection have been identified, and methods for their use provided.

In one aspect of the invention, compounds of Formula (I) are provided which are useful in the prevention and/or treatment of HCV infection. Without being limited to one theory, it is believed that the compounds of the present invention inhibit IRES-mediated initation, elongation and termination, i.e., translation. The compounds of Formula (I) may also be useful for inhibiting and/or treating other viral infections where the virus contains an IRES element. Such viruses include those of the picornavirus genus, such as by way of non-limiting example poliovirus, hepatitis A virus and rhinovirus; those of the coronaviridae genus, such as by way of non-limiting example SARS; those of the arbovirus genus; those of the flavivirus genus, such as by way of non-limiting example yellow fever, dengue, and West Nile virus; herpesviruses, such as by way of non-limiting example herpes simplex virus and Kaposi's sarcoma-associated herpesvirus, or any other virus with a similar mode of replication. Furthermore, compounds of the invention are also useful for inhibiting HIV, or any other virus with a similar mode of translation.

In another aspect of the invention, methods are provided for the prevention and/or treatment of HCV infection.

In yet another aspect of the invention, pharmaceutical compositions comprising the compounds of the invention for the prevention and/or treatment of HCV infection are provided.

In one embodiment, the invention is directed to methods for inhibiting HCV IRES-mediated initiation and translation comprising administering an amount of one or more compound of the invention, effective for inhibiting IRES-mediated initiation and translation, to a subject in need thereof.

Certain Embodiments

Embodiment 1. A pharmaceutical composition for the prevention or treatment of Hepatitis C viral (HCV) infection comprising a therapeutically effective amount of at least one compound having the following formula:

wherein:

X is:

hydrogen; a nitro group; a cyano group; a —COR_(a) group, where R_(a) is:

-   -   a C₁ to C₆ alkyl,     -   a C₆ to C₈ aryl optionally substituted with an alkoxy or a         halogen, or     -   a dialkyl-amino;         a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;         a formyl group;         a C₆ to C₈ aryl optionally substituted with an alkoxy; or         a 5 or 6-membered heteroaryl optionally substituted with:     -   a C₁ to C₆ alkyl,     -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or         more halogens, or     -   a 5 to 6 membered heteroaryl;

Y is:

a hydrogen; a haloalkyl; a halogen; an amino optionally substituted with one or more C₁ to C₆ alkyls; a benzofuran; a benzothiophene; a dibenzofuran; a dibenzothiophene; a benzothiazole; a naphthalene; an indole, optionally substituted on the nitrogen with a C₁ to C₆ alkyl;

where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined above, or an —SO₂R_(x), where R_(x) is as defined above; or

where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl; a —NHCOR_(e) group, where R_(e) is:

-   -   a C₁ to C₆ alkyl;     -   a C₆ to C₈ aryl optionally substituted with:         -   a C₁ to C₆ alkyl,         -   an alkoxy,         -   a cyano group,         -   a nitro group, or         -   a halogen;             a —NHCOOR_(x) group, where R_(x) is as defined above;             a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;             a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a             hydrogen and R_(h) is a C₆ to C₈ aryl optionally substituted             with an alkoxy;             a C₁ to C₆ alkyl;             a 5 or 6 membered heteroaryl, optionally substituted with:     -   a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl,     -   a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where         R_(x) is as defined above, or     -   an amino group;         a 5 or 6 membered heterocycle optionally substituted with:     -   a —COOR_(x) group, where R_(x) is as defined above, or     -   a —NHCOOR_(x) group, where R_(x) is as defined above;         a C₆ to C₈ aryl, optionally substituted with one or more of the         following:     -   an alkoxy, optionally substituted with:         -   an alkoxy,         -   a hydroxy,         -   one or more halogens,         -   a 5 or 6 membered heterocycle, optionally substituted with:             -   a C₁ to C₆ alkyl, or             -   a hydroxy,         -   an amino group optionally substituted with one or more C₁ to             C₆ alkyls,         -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and             R_(i) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a haloalkyl, or             -   a haloalkoxy,         -   a —NR_(j)COR_(k) group, where R_(k) is:             -   a C₁ to C₆ alkyl,             -   a hydrogen, or             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls, and R_(j) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a haloalkyl, or             -   a haloalkoxy,         -   a —N═N⁺═N⁻ group, or         -   a —COR_(l), where R_(l) is a 5 or 6 membered heterocycle             optionally substituted with a hydroxy,     -   an amino optionally substituted with one or more C₁ to C₆         alkyls,     -   a nitro group,     -   a C₁ to C₆ alkyl group, optionally substituted with:         -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or         -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,     -   a haloalkoxy,     -   a halogen,     -   a hydroxy,     -   a —COOR_(x) group, where R_(x) is as defined above,     -   a —COR_(m) group, where R_(m) is:         -   an amino optionally substituted with one or more C₁ to C₆             alkyls, where the C₁ to C₆ alkyls are optionally substituted             with:             -   a hydroxy             -   a 5 or 6 membered heterocycle,             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls,             -   an alkoxy,         -   a3 to 7 membered heterocycle, optionally substituted with a             C₁ to C₆ alkyl, optionally substituted with a dialkyl-amino,         -   a —NHR_(n) group, where R_(n) is:             -   a —CH₂CONH₂, or             -   a C₆ to C₈ aryl optionally substituted with:                 -   an alkyl,                 -   one or more halogens,                 -   a nitro group, or                 -   one or more alkoxys,     -   a —NR_(o)COR_(p) group, where R_(p) is:         -   a C₁ to C₆ alkyl optionally substituted with:             -   a halogen,             -   an alkoxy, or             -   a C₆ to C₈ aryl,         -   a 5 or 6 membered heterocycle,         -   a C₆ to C₈ aryl, optionally substituted with a halogen,         -   a 5 or 6 membered heteroaryl optionally substituted with one             or more C₁ to C₆ alkyls,         -   a hydrogen,

-   -   and where R_(o) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl, or         -   a haloalkoxy,     -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a haloalkyl,         -   a haloalkoxy, or         -   a —COR_(x) group, where R_(x) is as defined above,     -   and where R_(r) is:         -   a C₆ to C₈ aryl optionally substituted with:

-   -   -   -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or             -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a C₁ to C₆ alkyl optionally substituted with one or more of             the following:             -   a halogen,             -   an alkylene,             -   a C₆ to C₈ aryl, or             -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a —COOR_(x) group, where R_(x) is as defined above,

    -   a —NR_(t)COOR_(u) group, where R_(u) is:         -   a C₁ to C₁₂ alkyl, optionally substituted with:             -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆                 alkyl or an alkoxy,             -   an alkylene,             -   an alkoxy,             -   an alkyne,             -   a halogen, or             -   a 5 or 6 membered heterocycle,         -   a C₆ to C₈ aryl, optionally substituted with:             -   an alkoxy,             -   a halogen, or             -   a C₁ to C₆ alkyl, or         -   a 5 or 6 membered heterocycle,

    -   and R_(t) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl, or         -   a haloalkoxy,

    -   a —NR_(v)SO₂R_(w) group, where R_(v) is:         -   a hydrogen,         -   a —COR_(x), where R_(x) is as defined above, or         -   a C₁ to C₆ alkyl, optionally substituted with:             -   a halogen,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a —OCOR_(x) group, where R_(x) is as defined above,             -   a hydroxyl,             -   a hydroxyl, or             -   an alkoxy,

    -   and where R_(w) is:         -   a C₁ to C₆ alkyl optionally substituted with:             -   a halogen,             -   a haloalkyl,             -   a C₆ to C₈ aryl, or             -   a 5 or 6 membered heterocycle,         -   a C₂ to C₆ alkylene,         -   an alkyl- or dialkyl-amino optionally substituted with a             halogen,         -   a 5 or 6 membered heterocycle, or         -   a 5 or 6 membered heteroaryl optionally substituted with:             -   a C₁ to C₆ alkyl,             -   a 5 or 6 membered heterocycle, or

optionally substituted with a C₁ to C₆ alkyl, where R_(y) is a C₁ to C₆ alkyl or hydrogen,

-   -   where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally         substituted with a C₆ to C₈ aryl,     -   a —SR_(x) group, where R_(x) is as defined above,     -   a —SO₂R_(aa) group, where R_(aa) is:         -   a C₁ to C₆ alkyl,         -   an amino group,         -   an alkyl- or dialkyl-amino group optionally substituted with             a hydroxy or a —COOR_(x) group, where R_(x) is as defined             above,         -   a 5 or 6 membered heteroaryl,     -   a C₆ to C₈ aryl, or     -   a —NHR_(bb) group, where R_(bb) is:

-   -   -   a —C(═S)NH₂ group, or         -   a —PO(OR_(x))₂, where R_(x) is as defined above;

group, where R_(cc) is:

-   -   a naphthalene,     -   a 5 or 6 membered heteroaryl,

-   -   a C₆ to C₈ aryl, optionally substituted with one or more of the         following:         -   an alkoxy,         -   an hydroxy,         -   a halogen,         -   a C₁ to C₆ alkyl, optionally substituted with a cyano group,         -   an amino optionally substituted with one or more C₁ to C₆             alkyls,         -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,         -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen             or a C₁ to C₆ alkyl, optionally substituted with a halogen,             and R_(ff) is:             -   a hydrogen,             -   a haloalkyl,             -   a haloalkoxy,             -   a C₁ to C₆ alkyl, or             -   a —COR_(x), where R_(x) is as defined above,         -   a —NR_(gg)COR_(hh) group, where R_(hh) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl optionally substituted with:                 -   an alkoxy,                 -   a halogen, or                 -   an amino optionally substituted with one or more C₁                     to C₆ alkyls,             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls, where the alkyls are optionally substituted                 with a halogen,             -   a 5 or 6 membered heterocycle,             -   a 5 or 6 membered heteroaryl,         -   and R_(gg) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a haloalkoxy, or             -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl,         -   5 or 6 membered heterocycle groups,         -   an amino optionally substituted with one or more C₁ to C₆             alkyls,         -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined above,             and R_(ii) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a haloalkoxy,             -   a —COR_(x) group, where R_(x) is as defined above;

Z is:

a hydrogen; a C₁ to C₆ alkyl optionally substituted with:

-   -   an alkoxy,     -   one or more halogens, or     -   a C₆ to C₈ aryl;         a C₂ to C₆ alkylene;         a C₆ to C₈ aryl optionally substituted with an alkoxy or one or         more C₁ to C₆ alkyls;         a —COOR_(x) group, where R_(x) is as defined above; or

R is a hydrogen, a halogen or an alkoxy;

R₁ is:

a hydrogen; a hydroxy; a halogen; a haloalkyl; a nitro group; a 5 or 6 membered heteroaryl; a 5 or 6 membered heterocycle; an alkoxy optionally substituted with:

-   -   one or more halogens,     -   a C₆ to C₈ aryl, or     -   a 5 or 6 membered heterocycle;         a C₆ to C₈ aryl optionally substituted with an alkoxy;         a —COR_(x) group, where R_(x) is as defined above;         a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or         a 5 or 6 membered heterocycle; or         R₁ joins together with R₂ to form:

R₂ is:

a nitro group; a hydrogen; a halogen; a hydroxy group; a C₁ to C₆ alkyl group, optionally substituted with one or more halogens; an amino group; an alkoxy group optionally substituted with:

-   -   one or more halogens,     -   an —OCOR_(x) group, where R_(x) is as defined above,     -   a dialkyl-amino optionally substituted with an alkoxy,     -   a 5 or 6 membered heterocycle group optionally substituted with         a C₁ to C₆ alkyl,     -   a 5 or 6 membered heteroaryl group, or     -   a C₆ to C₈ aryl group;         a —COOR_(x) group, where R_(x) is as defined above;         a haloalkyl;         an amide group optionally substituted with:     -   a hydroxy group, or     -   a C₆ to C₈ aryl;         a 5 or 6 membered heteroaryl;         a —OCOR_(x) group, where R_(x) is as defined above;         a —NHCOR_(jj) group, where R_(jj) is:     -   an alkoxy, or     -   an amino optionally substituted with one or more C₁ to C₆         alkyls;         a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;         a —NHSO₂R_(x) group, where R_(x) is as defined above; or         R₂ joins together with R₁ to form:

R₃ is:

a hydrogen; or —CH₂OCOR_(x), and R_(x) is as defined above; or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and optionally at least one additional anti-HCV agents. Embodiment 2. The pharmaceutical composition of Embodiment 1, wherein said optional at least one additional anti-HCV agent is selected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a caspase inhibitor, a drug which targets inosine monophosphate dehydrogenase inhibitors (IMPDH), synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a glycosidase inhibitor, a helicase inhibitor, a Toll-like receptor agonist, and combinations thereof. Embodiment 3. The pharmaceutical composition of Embodiment 1, wherein X is selected from the group consisting of -hydrogen; -a cyano group; and -a —COR_(a) group, where R_(a) is: -a C₁ to C₆ alkyl, or -a dialkyl-amino. Embodiment 4. The pharmaceutical composition of Embodiment 1, wherein Y is selected from the group consisting of

Embodiment 5. The pharmaceutical composition of Embodiment 1, wherein Y is selected from the group consisting of

Embodiment 6. The pharmaceutical composition of Embodiment 1, wherein R is a hydrogen. Embodiment 7. The pharmaceutical composition of Embodiment 1, wherein R₁ is selected from the group consisting of a hydrogen, a nitro group, or an alkoxy. Embodiment 8. The pharmaceutical composition of Embodiment 1, wherein R₂ is selected from the group consisting of a hydroxy, a hydrogen, a haloalkyl group, a nitro group, an amide, —COOR_(x) or an alkoxy. Embodiment 9. The pharmaceutical composition of Embodiment 1, wherein R₃ is a hydrogen. Embodiment 10. The pharmaceutical composition of Embodiment 1, wherein said compound is selected from the compounds of Table A. Embodiment 11: The pharmaceutical composition of Embodiment 1 wherein said compound is selected from the compounds of Table B or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Embodiment 12. The pharmaceutical composition of Embodiment 17, wherein said composition further comprises at least one additional anti-HCV agent selected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a caspase inhibitor, a drug which targets inosine monophosphate dehydrogenase inhibitors (IMPDH), synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a glycosidase inhibitor, a helicase inhibitor, a Toll-like receptor agonist, and combinations thereof. Embodiment 13. A method for treating a subject for a Hepatitis C viral (HCV) infection comprising administering to said subject a pharmaceutical composition comprising an HCV inhibitory amount of at least one compound having the following formula:

wherein:

X is:

hydrogen; a nitro group; a cyano group; a —COR_(a) group, where R_(a) is:

-   -   a C₁ to C₆ alkyl,     -   a C₆ to C_(g) aryl optionally substituted with an alkoxy or a         halogen, or     -   a dialkyl-amino;         a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;         a formyl group;         a C₆ to C₈ aryl optionally substituted with an alkoxy; or         a 5 or 6-membered heteroaryl optionally substituted with:     -   a C₁ to C₆ alkyl,     -   a C₆ to C_(g) aryl optionally substituted with an alkoxy or one         or more halogens, or     -   a 5 to 6 membered heteroaryl;

Y is:

a hydrogen; a haloalkyl; a halogen; an amino optionally substituted with one or more C₁ to C₆ alkyls; a benzofuran; a benzothiophene; a dibenzofuran; a dibenzothiophene; a benzothiazole; a naphthalene; an indole, optionally substituted on the nitrogen with a C₁ to C₆ alkyl;

where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined above, or an —SO₂R_(x), where R_(x) is as defined above; or

where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl; a —NHCOR_(e) group, where R_(e) is:

-   -   a C₁ to C₆ alkyl;     -   a C₆ to C₈ aryl optionally substituted with:         -   a C₁ to C₆ alkyl,         -   an alkoxy,         -   a cyano group,         -   a nitro group, or         -   a halogen;             a —NHCOOR_(x) group, where R_(x) is as defined above;             a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;             a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a             hydrogen and R_(h) is a C₆ to C₈ aryl optionally substituted             with an alkoxy;             a C₁ to C₆ alkyl;             a 5 or 6 membered heteroaryl, optionally substituted with:     -   a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl,     -   a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where         R_(x) is as defined above, or     -   an amino group;         a 5 or 6 membered heterocycle optionally substituted with:     -   a —COOR_(x) group, where R_(x) is as defined above, or     -   a —NHCOOR_(x) group, where R_(x) is as defined above;         a C₆ to C₈ aryl, optionally substituted with one or more of the         following:     -   an alkoxy, optionally substituted with:         -   an alkoxy,         -   a hydroxy,         -   one or more halogens,         -   a 5 or 6 membered heterocycle, optionally substituted with:             -   a C₁ to C₆ alkyl, or             -   a hydroxy,         -   an amino group optionally substituted with one or more C₁ to             C₆ alkyls,         -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and             R_(i) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a haloalkyl, or             -   a haloalkoxy,         -   a —NR_(j)COR_(k) group, where R_(k) is:             -   a C₁ to C₆ alkyl,             -   a hydrogen, or             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls, and R_(j) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a haloalkyl, or             -   a haloalkoxy,         -   a —N═N⁺═N⁻ group, or         -   a —COR_(I), where R₁ is a 5 or 6 membered heterocycle             optionally substituted with a hydroxy,     -   an amino optionally substituted with one or more C₁ to C₆         alkyls,     -   a nitro group,     -   a C₁ to C₆ alkyl group, optionally substituted with:         -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or         -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,     -   a haloalkoxy,     -   a halogen,     -   a hydroxy,     -   a —COOR_(x) group, where R_(x) is as defined above,     -   a —COR_(m) group, where R_(m) is:         -   an amino optionally substituted with one or more C₁ to C₆             alkyls, where the C₁ to C₆ alkyls are optionally substituted             with:             -   a hydroxy             -   a 5 or 6 membered heterocycle,             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls,             -   an alkoxy,         -   a 3 to 7 membered heterocycle, optionally substituted with a             C₁ to C₆ alkyl, optionally substituted with a dialkyl-amino,         -   a —NHR_(n) group, where R_(n) is:             -   a —CH₂CONH₂, or             -   a C₆ to C₈ aryl optionally substituted with:                 -   an alkyl,                 -   one or more halogens,                 -   a nitro group, or                 -   one or more alkoxys,     -   a —NR_(o)COR_(p) group, where R_(p) is:         -   a C₁ to C₆ alkyl optionally substituted with:             -   a halogen,             -   an alkoxy, or             -   a C₆ to C₈ aryl,         -   a 5 or 6 membered heterocycle,         -   a C₆ to C₈ aryl, optionally substituted with a halogen,         -   a 5 or 6 membered heteroaryl optionally substituted with one             or more C₁ to C₆ alkyls,         -   a hydrogen,

-   -   and where R_(o) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl, or         -   a haloalkoxy,     -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a haloalkyl,         -   a haloalkoxy, or         -   a —COR_(x) group, where R_(x) is as defined above,     -   and where R_(r) is:         -   a C₆ to C₈ aryl optionally substituted with:

-   -   -   -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or             -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a C₁ to C₆ alkyl optionally substituted with one or more of             the following:             -   a halogen,             -   an alkylene,             -   a C₆ to C₈ aryl, or             -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a —COOR_(x) group, where R_(x) is as defined above,

    -   a —NR_(t)COOR_(u) group, where R_(u) is:         -   a C₁ to C₁₂ alkyl, optionally substituted with:             -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆                 alkyl or an alkoxy,             -   an alkylene,             -   an alkoxy,             -   an alkyne,             -   a halogen, or             -   a 5 or 6 membered heterocycle,         -   a C₆ to C₈ aryl, optionally substituted with:             -   an alkoxy,             -   a halogen, or             -   a C₁ to C₆ alkyl, or         -   a 5 or 6 membered heterocycle,

    -   and R_(t) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl, or         -   a haloalkoxy,

    -   a —NR_(v)SO₂R_(w) group, where R_(v) is:         -   a hydrogen,         -   a —COR_(x), where R_(x) is as defined above, or         -   a C₁ to C₆ alkyl, optionally substituted with:             -   a halogen,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a —OCOR_(x) group, where R_(x) is as defined above,             -   a hydroxyl,             -   a hydroxyl, or             -   an alkoxy,

    -   and where R_(w) is:         -   a C₁ to C₆ alkyl optionally substituted with:             -   a halogen,             -   a haloalkyl,             -   a C₆ to C_(g) aryl, or             -   a 5 or 6 membered heterocycle,         -   a C₂ to C₆ alkylene,         -   an alkyl- or dialkyl-amino optionally substituted with a             halogen,         -   a 5 or 6 membered heterocycle, or         -   a 5 or 6 membered heteroaryl optionally substituted with:             -   a C₁ to C₆ alkyl,             -   a 5 or 6 membered heterocycle, or

optionally substituted with a C₁ to C₆ alkyl, where R_(y) is a C₁ to C₆ alkyl or hydrogen,

-   -   where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally         substituted with a C₆ to C₈ aryl,     -   a —SR_(x) group, where R_(x) is as defined above,     -   a —SO₂R_(aa) group, where R_(aa) is:         -   a C₁ to C₆ alkyl,         -   an amino group,         -   an alkyl- or dialkyl-amino group optionally substituted with             a hydroxy or a —COOR_(x) group, where R_(x) is as defined             above,         -   a 5 or 6 membered heteroaryl,     -   a C₆ to C₈ aryl, or     -   a —NHR_(bb) group, where R_(bb) is:

-   -   -   a —C(═S)NH₂ group, or         -   a —PO(OR_(x))₂, where R_(x) is as defined above;

group, where R_(cc) is:

-   -   a naphthalene,     -   a 5 or 6 membered heteroaryl,

-   -   a C₆ to C₈ aryl, optionally substituted with one or more of the         following:         -   an alkoxy,         -   an hydroxy,         -   a halogen,         -   a C₁ to C₆ alkyl, optionally substituted with a cyano group,         -   an amino optionally substituted with one or more C₁ to C₆             alkyls,         -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,         -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen             or a C₁ to C₆ alkyl, optionally substituted with a halogen,             and R_(ff) is:             -   a hydrogen,             -   a haloalkyl,             -   a haloalkoxy,             -   a C₁ to C₆ alkyl, or             -   a —COR_(x), where R_(x) is as defined above,         -   a —NR_(gg)COR_(hh) group, where R_(hh) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl optionally substituted with:                 -   an alkoxy,                 -   a halogen, or                 -   an amino optionally substituted with one or more C₁                     to C₆ alkyls,             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls, where the alkyls are optionally substituted                 with a halogen,             -   a 5 or 6 membered heterocycle,             -   a 5 or 6 membered heteroaryl,         -   and R_(gg) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a haloalkoxy, or             -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl,         -   5 or 6 membered heterocycle groups,         -   an amino optionally substituted with one or more C₁ to C₆             alkyls,         -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined above,             and R_(ii) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a haloalkoxy,             -   a —COR_(x) group, where R_(x) is as defined above;

Z is:

a hydrogen; a C₁ to C₆ alkyl optionally substituted with:

-   -   an alkoxy,     -   one or more halogens, or     -   a C₆ to C₈ aryl;         a C₂ to C₆ alkylene;         a C₆ to C₈ aryl optionally substituted with an alkoxy or one or         more C₁ to C₆ alkyls;         a —COOR_(x) group, where R_(x) is as defined above; or

R is a hydrogen, a halogen or an alkoxy;

R₁ is:

a hydrogen; a hydroxy; a halogen; a haloalkyl; a nitro group; a 5 or 6 membered heteroaryl; a 5 or 6 membered heterocycle; an alkoxy optionally substituted with:

-   -   one or more halogens,     -   a C₆ to C₈ aryl, or     -   a 5 or 6 membered heterocycle;         a C₆ to C₈ aryl optionally substituted with an alkoxy;         a —COR_(x) group, where R_(x) is as defined above;         a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or         a 5 or 6 membered heterocycle; or         R₁ joins together with R₂ to form:

R₂ is:

a nitro group; a hydrogen; a halogen; a hydroxy group; a C₁ to C₆ alkyl group, optionally substituted with one or more halogens; an amino group; an alkoxy group optionally substituted with:

-   -   one or more halogens,     -   an —OCOR_(x) group, where R_(x) is as defined above,     -   a dialkyl-amino optionally substituted with an alkoxy,     -   a 5 or 6 membered heterocycle group optionally substituted with         a C₁ to C₆ alkyl,     -   a 5 or 6 membered heteroaryl group, or     -   a C₆ to C₈ aryl group;         a —COOR_(x) group, where R_(x) is as defined above;         a haloalkyl;         an amide group optionally substituted with:     -   a hydroxy group, or     -   a C₆ to C₈ aryl;         a 5 or 6 membered heteroaryl;         a —OCOR_(x) group, where R_(x) is as defined above;         a —NHCOR_(jj) group, where R_(jj) is:     -   an alkoxy, or     -   an amino optionally substituted with one or more C₁ to C₆         alkyls;         a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;         a —NHSO₂R_(x) group, where R_(x) is as defined above; or         R₂ joins together with R₁ to form:

R₃ is:

a hydrogen; or —CH₂OCOR_(x), and R_(x) is as defined above; or a pharmaceutically acceptable salt thereof and a pharamceutically acceptable excipient. Embodiment 14. The method of Embodiment 13, wherein said pharmaceutical composition further comprises at least one additional anti-HCV agent. Embodiment 15. The method of Embodiment 14, wherein said at least one additional anti-HCV agent is selected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a caspase inhibitor, a drug which targets inosine monophosphate dehydrogenase inhibitors (IMPDH), synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a glycosidase inhibitor, a helicase inhibitor, a Toll-like receptor agonist, and combinations thereof. Embodiment 16. The method of Embodiment 13, wherein X is selected from the group consisting of -hydrogen; -a cyano group; and -a —COR_(a) group, where R_(a) is: -a C₁ to C₆ alkyl, or -a dialkyl-amino. Embodiment 17. The method of Embodiment 13, wherein Y is selected from the group consisting of

Embodiment 18. The method of Embodiment 13, wherein Y is selected from the group consisting of

Embodiment 19. The method of Embodiment 13, wherein R is a hydrogen. Embodiment 20. The method of Embodiment 13, wherein R₁ is selected from the group consisting of -a hydrogen; -a halogen; -a nitro group; -a 5 or 6 membered heterocycle; -an alkoxy optionally substituted with: -a C₆ to C₈ aryl; -a C₆ to C₈ aryl optionally substituted with an alkoxy Embodiment 21. The method of Embodiment 13, wherein R₂ is selected from the group consisting of -a nitro group; -a hydrogen; -a halogen; -a hydroxy group; -a C₁ to C₆ alkyl group, optionally substituted with one or more halogens; -an alkoxy group optionally substituted with: -one or more halogens, -an —OCOR_(x) group, where R_(x) is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C₁ to C₆ alkyl, or -a 5 or 6 membered heteroaryl group; -an amide group; and -a —NHSO₂R_(x) group, where R_(x) is as defined above Embodiment 22. The method of Embodiment 13, wherein R₃ is a hydrogen. Embodiment 23. The method of Embodiment 13, wherein said compound is selected from the compounds of Table A. Embodiment 24. The method of Embodiment 13, wherein said compound is selected from the compounds of Table B. Embodiment 25. A method for treating or preventing infection by a virus in a subject, wherein said virus comprises a internal ribosome entry site (IRES), comprising administering to said subject a pharmaceutical composition comprising a viral inhibitory amount of one or more compound having the following formula:

wherein:

X is:

hydrogen; a nitro group; a cyano group; a —COR_(a) group, where R_(a) is:

-   -   a C₁ to C₆ alkyl,     -   a C₆ to C₈ aryl optionally substituted with an alkoxy or a         halogen, or     -   a dialkyl-amino;         a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;         a formyl group;         a C₆ to C₈ aryl optionally substituted with an alkoxy; or         a 5 or 6-membered heteroaryl optionally substituted with:     -   a C₁ to C₆ alkyl,     -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or         more halogens, or     -   a 5 to 6 membered heteroaryl;

Y is:

a hydrogen; a haloalkyl; a halogen; an amino optionally substituted with one or more C₁ to C₆ alkyls; a benzofuran; a benzothiophene; a dibenzofuran; a dibenzothiophene; a benzothiazole; a naphthalene; an indole, optionally substituted on the nitrogen with a C₁ to C₆ alkyl;

where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined above, or an —SO₂R_(x), where R_(x) is as defined above; or

where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl; a —NHCOR_(e) group, where R_(e) is:

-   -   a C₁ to C₆ alkyl;     -   a C₆ to C₈ aryl optionally substituted with:         -   a C₁ to C₆ alkyl,         -   an alkoxy,         -   a cyano group,         -   a nitro group, or         -   a halogen;             a —NHCOOR_(x) group, where R_(x) is as defined above;             a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;             a —NR_(g)R_(h) group, where R₈ is a C₁ to C₆ alkyl or a             hydrogen and R_(h) is a C₆ to C₈ aryl optionally substituted             with an alkoxy;             a C₁ to C₆ alkyl;             a 5 or 6 membered heteroaryl, optionally substituted with:     -   a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl,     -   a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where         R_(x) is as defined above, or     -   an amino group;         a 5 or 6 membered heterocycle optionally substituted with:     -   a —COOR_(x) group, where R_(x) is as defined above, or     -   a —NHCOOR_(x) group, where R_(x) is as defined above;         a C₆ to C₈ aryl, optionally substituted with one or more of the         following:     -   an alkoxy, optionally substituted with:         -   an alkoxy,         -   a hydroxy,         -   one or more halogens,         -   a 5 or 6 membered heterocycle, optionally substituted with:             -   a C₁ to C₆ alkyl, or             -   a hydroxy,         -   an amino group optionally substituted with one or more C₁ to             C₆ alkyls,         -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and             R_(i) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a haloalkyl, or             -   a haloalkoxy,         -   a —NR_(j)COR_(k) group, where R_(k) is:             -   a C₁ to C₆ alkyl,             -   a hydrogen, or             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls, and R_(j) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a haloalkyl, or             -   a haloalkoxy,         -   a —N═N⁺═N⁻ group, or         -   a —COR₁, where R₁ is a 5 or 6 membered heterocycle             optionally substituted with a hydroxy,     -   an amino optionally substituted with one or more C₁ to C₆         alkyls,     -   a nitro group,     -   a C₁ to C₆ alkyl group, optionally substituted with:         -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or         -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,     -   a haloalkoxy,     -   a halogen,     -   a hydroxy,     -   a —COOR_(x) group, where R_(x) is as defined above,     -   a —COR_(m) group, where R_(m) is:         -   an amino optionally substituted with one or more C₁ to C₆             alkyls, where the C₁ to C₆ alkyls are optionally substituted             with:             -   a hydroxy             -   a 5 or 6 membered heterocycle,             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls,             -   an alkoxy,         -   a3 to 7 membered heterocycle, optionally substituted with a             C₁ to C₆ alkyl, optionally substituted with a dialkyl-amino,         -   a —NHR_(n) group, where R_(n) is:             -   a —CH₂CONH₂, or             -   a C₆ to C₈ aryl optionally substituted with:                 -   an alkyl,                 -   one or more halogens,                 -   a nitro group, or                 -   one or more alkoxys,     -   a —NR_(o)COR_(p) group, where R_(p) is:         -   a C₁ to C₆ alkyl optionally substituted with:             -   a halogen,             -   an alkoxy, or             -   a C₆ to C₈ aryl,         -   a 5 or 6 membered heterocycle,         -   a C₆ to C₈ aryl, optionally substituted with a halogen,         -   a 5 or 6 membered heteroaryl optionally substituted with one             or more C₁ to C₆ alkyls,         -   a hydrogen,

-   -   and where R_(o) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl, or         -   a haloalkoxy,     -   a —NR_(q)CON_(q)R_(r) group, where R_(q) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a haloalkyl,         -   a haloalkoxy, or         -   a —COR_(x) group, where R_(x) is as defined above,     -   and where R_(r) is:         -   a C₆ to C₈ aryl optionally substituted with:

-   -   -   -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or             -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a C₁ to C₆ alkyl optionally substituted with one or more of             the following:             -   a halogen,             -   an alkylene,             -   a C₆ to C₈ aryl, or             -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a —COOR_(x) group, where R_(x) is as defined above,

    -   a —NR_(t)COOR_(u) group, where R_(u) is:         -   a C₁ to C₁₂ alkyl, optionally substituted with:             -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆                 alkyl or an alkoxy,             -   an alkylene,             -   an alkoxy,             -   an alkyne,             -   a halogen, or             -   a 5 or 6 membered heterocycle,         -   a C₆ to C₈ aryl, optionally substituted with:             -   an alkoxy,             -   a halogen, or             -   a C₁ to C₆ alkyl, or         -   a 5 or 6 membered heterocycle,

    -   and R_(t) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl, or         -   a haloalkoxy,

    -   a —NR_(v)SO₂R_(w) group, where R_(v) is:         -   a hydrogen,         -   a —COR_(x), where R_(x) is as defined above, or         -   a C₁ to C₆ alkyl, optionally substituted with:             -   a halogen,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a —OCOR_(x) group, where R_(x) is as defined above,             -   a hydroxyl,             -   a hydroxyl, or             -   an alkoxy,

    -   and where R_(w) is:         -   a C₁ to C₆ alkyl optionally substituted with:             -   a halogen,             -   a haloalkyl,             -   a C₆ to C₈ aryl, or             -   a 5 or 6 membered heterocycle,

    -   a C₂ to C₆ alkylene,

    -   an alkyl- or dialkyl-amino optionally substituted with a         halogen,

    -   a 5 or 6 membered heterocycle, or

    -   a 5 or 6 membered heteroaryl optionally substituted with:         -   a C₁ to C₆ alkyl,         -   a 5 or 6 membered heterocycle, or

optionally substituted with a C₁ to C₆ alkyl, where R_(y) is a C₁ to C₆ alkyl or hydrogen,

-   -   where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally         substituted with a C₆ to C₈ aryl,     -   a —SR_(x) group, where R_(x) is as defined above,     -   a —SO₂R_(aa) group, where R_(aa) is:         -   a C₁ to C₆ alkyl,         -   an amino group,         -   an alkyl- or dialkyl-amino group optionally substituted with             a hydroxy or a —COOR_(x) group, where R_(x) is as defined             above,         -   a 5 or 6 membered heteroaryl,     -   a C₆ to C₈ aryl, or     -   a —NHR_(bb) group, where R_(bb) is:

-   -   -   a —C(═S)NH₂ group, or         -   a —PO(OR_(x))₂, where R_(x) is as defined above;

group, where R_(cc) is:

-   -   a naphthalene,     -   a 5 or 6 membered heteroaryl,

-   -   a C₆ to C₈ aryl, optionally substituted with one or more of the         following:         -   an alkoxy,         -   an hydroxy,         -   a halogen,         -   a C₁ to C₆ alkyl, optionally substituted with a cyano group,         -   an amino optionally substituted with one or more C₁ to C₆             alkyls,         -   a —NHPOR_(x)R_(x) where R_(x) is as defined above,         -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen             or a C₁ to C₆ alkyl, optionally substituted with a halogen,             and R_(ff) is:             -   a hydrogen,             -   a haloalkyl,             -   a haloalkoxy,             -   a C₁ to C₆ alkyl, or             -   a —COR_(x), where R_(x) is as defined above,         -   a —NR_(gg)COR_(hh) group, where R_(hh) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl optionally substituted with:                 -   an alkoxy,                 -   a halogen, or                 -   an amino optionally substituted with one or more C₁                     to C₆ alkyls,             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls, where the alkyls are optionally substituted                 with a halogen,             -   a 5 or 6 membered heterocycle,             -   a 5 or 6 membered heteroaryl,         -   and R_(gg) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a haloalkoxy, or             -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl,         -   5 or 6 membered heterocycle groups,         -   an amino optionally substituted with one or more C₁ to C₆             alkyls,         -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined above,             and R_(ii) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a haloalkoxy,             -   a —COR_(x) group, where R_(x) is as defined above;

Z is:

a hydrogen; a C₁ to C₆ alkyl optionally substituted with:

-   -   an alkoxy,     -   one or more halogens, or     -   a C₆ to C₈ aryl;     -   a C₂ to C₆ alkylene;     -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or         more C₁ to C₆ alkyls;     -   a —COOR_(x) group, where R_(x) is as defined above; or

R is a hydrogen, a halogen or an alkoxy;

R₁ is:

a hydrogen; a hydroxy; a halogen; a haloalkyl; a nitro group; a 5 or 6 membered heteroaryl; a 5 or 6 membered heterocycle; an alkoxy optionally substituted with:

-   -   one or more halogens,     -   a C₆ to C₈ aryl, or     -   a 5 or 6 membered heterocycle;         a C₆ to C₈ aryl optionally substituted with an alkoxy;         a —COR_(x) group, where R_(x) is as defined above;         a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or         a 5 or 6 membered heterocycle; or         R₁ joins together with R₂ to form:

R₂ is:

a nitro group; a hydrogen; a halogen; a hydroxy group; a C₁ to C₆ alkyl group, optionally substituted with one or more halogens; an amino group; an alkoxy group optionally substituted with:

-   -   one or more halogens,     -   an —OCOR_(x) group, where R_(x) is as defined above,     -   a dialkyl-amino optionally substituted with an alkoxy,     -   a 5 or 6 membered heterocycle group optionally substituted with         a C₁ to C₆ alkyl,     -   a 5 or 6 membered heteroaryl group, or     -   a C₆ to C₈ aryl group;         a —COOR_(x) group, where R_(x) is as defined above;         a haloalkyl;         an amide group optionally substituted with:     -   a hydroxy group, or     -   a C₆ to C₈ aryl;         a 5 or 6 membered heteroaryl;         a —OCOR_(x) group, where R_(x) is as defined above;         a —NHCOR_(jj) group, where R_(jj) is:     -   an alkoxy, or     -   an amino optionally substituted with one or more C₁ to C₆         alkyls;         a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;         a —NHSO₂R_(x) group, where R_(x) is as defined above; or         R₂ joins together with R₁ to form:

R₃ is:

a hydrogen; or —CH₂OCOR_(x), and R_(x) is as defined above; and/or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient. Embodiment 33. The method of Embodiment 32 wherein said pharmaceutical composition further comprises at least one additional anti-viral agent. Embodiment 34. The method of Embodiment 33, wherein said at least one additional anti-viral agent is elected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a caspase inhibitor, a drug which targets inosine monophosphate dehydrogenase inhibitors (IMPDH), synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a glycosidase inhibitor, a helicase inhibitor, and a Toll-like receptor agonist. Embodiment 26. A compound selected from the group consisting of the following:

Embodiment 27. A compound selected from the group consisting of the following:

Embodiment 27. A compound selected from the group consisting of the following:

Embodiment 29. A pharmaceutical composition for affecting viral IRES activity in a subject infected with a virus, comprising one or more compound having the following formula:

wherein:

X is:

hydrogen; a nitro group; a cyano group; a —COR_(a) group, where R_(a) is:

-   -   a C₁ to C₆ alkyl,     -   a C₆ to C₈ aryl optionally substituted with an alkoxy or a         halogen, or     -   a dialkyl-amino;         a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;         a formyl group;         a C₆ to C₈ aryl optionally substituted with an alkoxy; or         a 5 or 6-membered heteroaryl optionally substituted with:     -   a C₁ to C₆ alkyl,     -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or         more halogens, or     -   a 5 to 6 membered heteroaryl;

Y is:

a hydrogen; a haloalkyl; a halogen; an amino optionally substituted with one or more C₁ to C₆ alkyls; a benzofuran; a benzothiophene; a dibenzofuran; a dibenzothiophene; a benzothiazole; a naphthalene; an indole, optionally substituted on the nitrogen with a C₁ to C₆ alkyl;

where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined above, or an —SO₂R_(x), where R_(x) is as defined above; or

where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl; a —NHCOR_(e) group, where R_(e) is:

-   -   a C₁ to C₆ alkyl;     -   a C₆ to C₈ aryl optionally substituted with:         -   a C₁ to C₆ alkyl,         -   an alkoxy,         -   a cyano group,         -   a nitro group, or         -   a halogen;             a —NHCOOR_(x) group, where R_(x) is as defined above;             a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;             a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a             hydrogen and R_(h) is a C₆ to C₈ aryl optionally substituted             with an alkoxy;             a C₁ to C₆ alkyl;             a 5 or 6 membered heteroaryl, optionally substituted with:     -   a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl,     -   a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where         R_(x) is as defined above, or     -   an amino group;         a 5 or 6 membered heterocycle optionally substituted with:     -   a —COOR_(x) group, where R_(x) is as defined above, or     -   a —NHCOOR_(x) group, where R_(x) is as defined above;         a C₆ to C₈ aryl, optionally substituted with one or more of the         following:     -   an alkoxy, optionally substituted with:         -   an alkoxy,     -   a hydroxy,         -   one or more halogens,         -   a 5 or 6 membered heterocycle, optionally substituted with:             -   a C₁ to C₆ alkyl, or             -   a hydroxy,         -   an amino group optionally substituted with one or more C₁ to             C₆ alkyls,         -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and             R_(i) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a haloalkyl, or             -   a haloalkoxy,         -   a —NR_(j)COR_(k) group, where R_(k) is:             -   a C₁ to C₆ alkyl,             -   a hydrogen, or             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls,         -   and R_(j) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a haloalkyl, or             -   a haloalkoxy,         -   a —N═N⁺═N⁻ group, or         -   a —COR_(l), where R_(l) is a 5 or 6 membered heterocycle             optionally substituted with a hydroxy,     -   an amino optionally substituted with one or more C₁ to C₆         alkyls,     -   a nitro group,     -   a C₁ to C₆ alkyl group, optionally substituted with:         -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or         -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,     -   a haloalkoxy,     -   a halogen,     -   a hydroxy,     -   a —COOR_(x) group, where R_(x) is as defined above,     -   a —COR_(m) group, where R_(m) is:         -   an amino optionally substituted with one or more C₁ to C₆             alkyls, where the C₁ to C₆ alkyls are optionally substituted             with:             -   a hydroxy             -   a 5 or 6 membered heterocycle,             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls,             -   an alkoxy,         -   a 3 to 7 membered heterocycle, optionally substituted with a             C₁ to C₆ alkyl, optionally substituted with a dialkyl-amino,         -   a —NHR_(n) group, where R_(n) is:             -   a —CH₂CONH₂, or             -   a C₆ to C₈ aryl optionally substituted with:                 -   an alkyl,                 -   one or more halogens,                 -   a nitro group, or                 -   one or more alkoxys,     -   a —NR_(o)COR_(p) group, where R_(p) is:         -   a C₁ to C₆ alkyl optionally substituted with:             -   a halogen,             -   an alkoxy, or             -   a C₆ to C₈ aryl,         -   a 5 or 6 membered heterocycle,         -   a C₆ to C₈ aryl, optionally substituted with a halogen,         -   a 5 or 6 membered heteroaryl optionally substituted with one             or more C₁ to C₆ alkyls,         -   a hydrogen,

-   -   and where R_(o) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl, or         -   a haloalkoxy,     -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a haloalkyl,         -   a haloalkoxy, or         -   a —COR_(x) group, where R_(x) is as defined above,     -   and where R_(r) is:         -   a C₆ to C₈ aryl optionally substituted with:

-   -   -   -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or             -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a C₁ to C₆ alkyl optionally substituted with one or more of             the following:             -   a halogen,             -   an alkylene,             -   a C₆ to C₈ aryl, or             -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a —COOR_(x) group, where R_(x) is as defined above,

    -   a —NR_(t)COOR_(u) group, where R_(u) is:         -   a C₁ to C₁₂ alkyl, optionally substituted with:             -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆                 alkyl or an alkoxy,             -   an alkylene,             -   an alkoxy,             -   an alkyne,             -   a halogen, or             -   a 5 or 6 membered heterocycle,         -   a C₆ to C₈ aryl, optionally substituted with:             -   an alkoxy,             -   a halogen, or             -   a C₁ to C₆ alkyl, or         -   a 5 or 6 membered heterocycle,

    -   and R_(t) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl, or         -   a haloalkoxy,

    -   a —NR_(v)SO₂R_(w) group, where R_(v) is:         -   a hydrogen,         -   a —COR_(x), where R_(x) is as defined above, or         -   a C₁ to C₆ alkyl, optionally substituted with:             -   a halogen,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a —OCOR_(x) group, where R_(x) is as defined above,             -   a hydroxyl,             -   a hydroxyl, or             -   an alkoxy,

    -   and where R_(w) is:         -   a C₁ to C₆ alkyl optionally substituted with:             -   a halogen,             -   a haloalkyl,             -   a C₆ to C₈ aryl, or             -   a 5 or 6 membered heterocycle,         -   a C₂ to C₆ alkylene,         -   an alkyl- or dialkyl-amino optionally substituted with a             halogen,         -   a 5 or 6 membered heterocycle, or         -   a 5 or 6 membered heteroaryl optionally substituted with:             -   a C₁ to C₆ alkyl,             -   a 5 or 6 membered heterocycle, or

optionally substituted with a C₁ to C₆ alkyl, where R_(y) is a C₁ to C₆ alkyl or hydrogen,

-   -   where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally         substituted with a C₆ to C₈ aryl,     -   a —SR_(x) group, where R_(x) is as defined above,     -   a —SO₂R_(aa) group, where R_(aa) is:         -   a C₁ to C₆ alkyl,         -   an amino group,         -   an alkyl- or dialkyl-amino group optionally substituted with             a hydroxy or a —COOR_(x) group, where R_(x) is as defined             above,         -   a 5 or 6 membered heteroaryl,     -   a C₆ to C₈ aryl, or     -   a —NHR_(bb) group, where R_(bb) is:

-   -   -   a —C(═S)NH₂ group, or         -   a —PO(OR_(x))₂, where R_(x) is as defined above;

group, where R_(cc) is:

-   -   a naphthalene,     -   a 5 or 6 membered heteroaryl,

-   -   a C₆ to C₈ aryl, optionally substituted with one or more of the         following:         -   an alkoxy,         -   an hydroxy,         -   a halogen,         -   a C₁ to C₆ alkyl, optionally substituted with a cyano group,         -   an amino optionally substituted with one or more C₁ to C₆             alkyls,         -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,         -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen             or a C₁ to C₆ alkyl, optionally substituted with a halogen,             and R_(ff) is:             -   a hydrogen,             -   a haloalkyl,             -   a haloalkoxy,             -   a C₁ to C₆ alkyl, or             -   a —COR_(x), where R_(x) is as defined above,         -   a —NR_(gg)COR_(hh) group, where R_(hh) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl optionally substituted with:                 -   an alkoxy,                 -   a halogen, or                 -   an amino optionally substituted with one or more C₁                     to C₆ alkyls,             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls, where the alkyls are optionally substituted                 with a halogen,             -   a 5 or 6 membered heterocycle,             -   a 5 or 6 membered heteroaryl,         -   and R_(gg) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a haloalkoxy, or             -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl,         -   5 or 6 membered heterocycle groups,         -   an amino optionally substituted with one or more C₁ to C₆             alkyls,         -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined above,             and R_(ii) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a haloalkoxy,             -   a —COR_(x) group, where R_(x) is as defined above;

Z is:

a hydrogen; a C₁ to C₆ alkyl optionally substituted with:

-   -   an alkoxy,     -   one or more halogens, or         a C₆ to C₈ aryl;         a C₂ to C₆ alkylene;         a C₆ to C₈ aryl optionally substituted with an alkoxy or one or         more C₁ to C₆ alkyls;         a —COOR_(x) group, where R_(x) is as defined above; or

R is a hydrogen, a halogen or an alkoxy;

R₁ is:

a hydrogen; a hydroxy; a halogen; a haloalkyl; a nitro group; a 5 or 6 membered heteroaryl; a 5 or 6 membered heterocycle; an alkoxy optionally substituted with:

-   -   one or more halogens,     -   a C₆ to C₈ aryl, or     -   a 5 or 6 membered heterocycle;         a C₆ to C₈ aryl optionally substituted with an alkoxy;         a —COR_(x) group, where R_(x) is as defined above;         a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or         a 5 or 6 membered heterocycle; or         R₁ joins together with R₂ to form:

R₂ is:

a nitro group; a hydrogen; a halogen; a hydroxy group; a C₁ to C₆ alkyl group, optionally substituted with one or more halogens; an amino group; an alkoxy group optionally substituted with:

-   -   one or more halogens,     -   an —OCOR_(x) group, where R_(x) is as defined above,     -   a dialkyl-amino optionally substituted with an alkoxy,     -   a 5 or 6 membered heterocycle group optionally substituted with         a C₁ to C₆ alkyl,     -   a 5 or 6 membered heteroaryl group, or     -   a C₆ to C₈ aryl group;         a —COOR_(x) group, where R_(x) is as defined above;         a haloalkyl;         an amide group optionally substituted with:     -   a hydroxy group, or     -   a C₆ to C₈ aryl;         a 5 or 6 membered heteroaryl;         a —OCOR_(x) group, where R_(x) is as defined above;         a —NHCOR_(jj) group, where R_(jj) is:     -   an alkoxy, or     -   an amino optionally substituted with one or more C₁ to C₆         alkyls;         a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;         a —NHSO₂R_(x) group, where R_(x) is as defined above; or         R₂ joins together with R₁ to form:

R₃ is:

a hydrogen; or —CH₂OCOR_(x), and R_(x) is as defined above; or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and optionally one or more compound known in the art to affect IRES activity. Embodiment 30. The pharmaceutical composition of Embodiment 29, wherein said one or more compound known in the art to affect IRES activity affects IRES mediated translation of the single ORF encoding the polyprotein. Embodiment 31. A method for affecting viral IRES activity in a subject infected with a virus, comprising administering to said subject one or more compound having the following formula:

wherein:

X is:

hydrogen; a nitro group; a cyano group; a —COR_(a) group, where R_(a) is:

-   -   a C₁ to C₆ alkyl,     -   a C₆ to C₈ aryl optionally substituted with an alkoxy or a         halogen, or     -   a dialkyl-amino;         a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;         a formyl group;         a C₆ to C₈ aryl optionally substituted with an alkoxy; or         a 5 or 6-membered heteroaryl optionally substituted with:     -   a C₁ to C₆ alkyl,     -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or         more halogens, or     -   a 5 to 6 membered heteroaryl;

Y is:

a hydrogen; a haloalkyl; a halogen; an amino optionally substituted with one or more C₁ to C₆ alkyls; a benzofuran; a benzothiophene; a dibenzofuran; a dibenzothiophene; a benzothiazole; a naphthalene; an indole, optionally substituted on the nitrogen with a C₁ to C₆ alkyl;

where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined above, or an —SO₂R_(x), where R_(x) is as defined above; or

where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl; a —NHCOR_(e) group, where R_(e) is:

-   -   a C₁ to C₆ alkyl;     -   a C₆ to C₈ aryl optionally substituted with:         -   a C₁ to C₆ alkyl,         -   an alkoxy,         -   a cyano group,         -   a nitro group, or         -   a halogen;     -   a —NHCOOR_(x) group, where R_(x) is as defined above;     -   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;     -   a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a         hydrogen and R_(h) is a C₆ to C₈ aryl optionally substituted         with an alkoxy;         a C₁ to C₆ alkyl;         a 5 or 6 membered heteroaryl, optionally substituted with:     -   a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl,     -   a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where         R_(x) is as defined above, or     -   an amino group;         a 5 or 6 membered heterocycle optionally substituted with:     -   a —COOR_(x) group, where R_(x) is as defined above, or     -   a —NHCOOR_(x) group, where R_(x) is as defined above;         a C₆ to C₈ aryl, optionally substituted with one or more of the         following:     -   an alkoxy, optionally substituted with:         -   an alkoxy,         -   a hydroxy,         -   one or more halogens,         -   a 5 or 6 membered heterocycle, optionally substituted with:             -   a C₁ to C₆ alkyl, or             -   a hydroxy,         -   an amino group optionally substituted with one or more C₁ to             C₆ alkyls,         -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and             R_(i) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a haloalkyl, or             -   a haloalkoxy,         -   a —NR_(j)COR_(k) group, where R_(k) is:             -   a C₁ to C₆ alkyl,             -   a hydrogen, or             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls,         -   and R_(j) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a haloalkyl, or             -   a haloalkoxy,         -   a —N═N⁺═N⁻ group, or         -   a —COR_(l), where R_(l) is a 5 or 6 membered heterocycle             optionally substituted with a hydroxy,     -   an amino optionally substituted with one or more C₁ to C₆         alkyls,     -   a nitro group,     -   a C₁ to C₆ alkyl group, optionally substituted with:         -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or         -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,     -   a haloalkoxy,     -   a halogen,     -   a hydroxy,     -   a —COOR_(x) group, where R_(x) is as defined above,     -   a —COR_(m) group, where R_(m) is:         -   an amino optionally substituted with one or more C₁ to C₆             alkyls, where the C₁ to C₆ alkyls are optionally substituted             with:             -   a hydroxy             -   a 5 or 6 membered heterocycle,             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls,             -   an alkoxy,         -   a3 to 7 membered heterocycle, optionally substituted with a             C₁ to C₆ alkyl, optionally substituted with a dialkyl-amino,         -   a —NHR_(n) group, where R_(n) is:             -   a —CH₂CONH₂, or             -   a C₆ to C₈ aryl optionally substituted with:                 -   an alkyl,                 -   one or more halogens,                 -   a nitro group, or                 -   one or more alkoxys,     -   a —NR_(o)COR_(p) group, where R_(p) is:         -   a C₁ to C₆ alkyl optionally substituted with:             -   a halogen,             -   an alkoxy, or             -   a C₆ to C₈ aryl,         -   a 5 or 6 membered heterocycle,         -   a C₆ to C₈ aryl, optionally substituted with a halogen,         -   a 5 or 6 membered heteroaryl optionally substituted with one             or more C₁ to C₆ alkyls,         -   a hydrogen,

-   -   and where R_(o) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl, or         -   a haloalkoxy,     -   a —NR_(q)CONR_(q)R_(f) group, where R_(q) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a haloalkyl,         -   a haloalkoxy, or         -   a —COR_(x) group, where R_(x) is as defined above,     -   and where R_(r) is:         -   a C₆ to C₈ aryl optionally substituted with:

-   -   -   -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or             -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a C₁ to C₆ alkyl optionally substituted with one or more of             the following:             -   a halogen,             -   an alkylene,             -   a C₆ to C₈ aryl, or             -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a —COOR_(x) group, where R_(x) is as defined above,

    -   a —NR_(t)COOR_(u) group, where R_(u) is:         -   a C₁ to C₁₂ alkyl, optionally substituted with:             -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆                 alkyl or an alkoxy,             -   an alkylene,             -   an alkoxy,             -   an alkyne,             -   a halogen, or             -   a 5 or 6 membered heterocycle,         -   a C₆ to C₈ aryl, optionally substituted with:             -   an alkoxy,             -   a halogen, or             -   a C₁ to C₆ alkyl, or         -   a 5 or 6 membered heterocycle,

    -   and R_(t) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl, or         -   a haloalkoxy,

    -   a —NR_(v)SO₂R_(w) group, where R_(v) is:         -   a hydrogen,         -   a —COR_(x), where R_(x) is as defined above, or         -   a C₁ to C₆ alkyl, optionally substituted with:             -   a halogen,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a —OCOR_(x) group, where R_(x) is as defined above,             -   a hydroxyl,             -   a hydroxyl, or             -   an alkoxy,

    -   and where R_(w) is:         -   a C₁ to C₆ alkyl optionally substituted with:             -   a halogen,             -   a haloalkyl,             -   a C₆ to C₈ aryl, or             -   a 5 or 6 membered heterocycle,         -   a C₂ to C₆ alkylene,         -   an alkyl- or dialkyl-amino optionally substituted with a             halogen,         -   a 5 or 6 membered heterocycle, or         -   a 5 or 6 membered heteroaryl optionally substituted with:             -   a C₁ to C₆ alkyl,             -   a 5 or 6 membered heterocycle, or

optionally substituted with a C₁ to C₆ alkyl, where R_(y) is a C₁ to C₆ alkyl or hydrogen,

-   -   where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally         substituted with a C₆ to C₈ aryl,     -   a —SR_(x) group, where R_(x) is as defined above,     -   a —SO₂R_(aa) group, where R_(aa) is:         -   a C₁ to C₆ alkyl,         -   an amino group,         -   an alkyl- or dialkyl-amino group optionally substituted with             a hydroxy or a —COOR_(x) group, where R_(x) is as defined             above,         -   a 5 or 6 membered heteroaryl,     -   a C₆ to C₈ aryl, or     -   a —NHR_(bb) group, where R_(bb) is:

-   -   -   a —C(═S)NH₂ group, or         -   a —PO(OR_(x))₂, where R_(x) is as defined above;

group, where R_(cc) is:

-   -   a naphthalene,     -   a 5 or 6 membered heteroaryl,

-   -   a C₆ to C₈ aryl, optionally substituted with one or more of the         following:         -   an alkoxy,         -   an hydroxy,         -   a halogen,         -   a C₁ to C₆ alkyl, optionally substituted with a cyano group,         -   an amino optionally substituted with one or more C₁ to C₆             alkyls,         -   a —NHPOR_(x)R_(x) where R_(x) is as defined above,         -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen             or a C₁ to C₆ alkyl, optionally substituted with a halogen,             and R_(ff) is:             -   a hydrogen,             -   a haloalkyl,             -   a haloalkoxy,             -   a C₁ to C₆ alkyl, or             -   a —COR_(x), where R_(x) is as defined above,         -   a —NR_(gg)COR_(hh) group, where R_(hh) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl optionally substituted with:                 -   an alkoxy,                 -   a halogen, or                 -   an amino optionally substituted with one or more C₁                     to C₆ alkyls,             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls, where the alkyls are optionally substituted                 with a halogen,             -   a 5 or 6 membered heterocycle,             -   a 5 or 6 membered heteroaryl,         -   and R_(gg) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a haloalkoxy, or             -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl,         -   5 or 6 membered heterocycle groups,         -   an amino optionally substituted with one or more C₁ to C₆             alkyls,         -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined above,             and R_(ii) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a haloalkoxy,             -   a —COR_(x) group, where R_(x) is as defined above;

Z is:

a hydrogen; a C₁ to C₆ alkyl optionally substituted with:

-   -   an alkoxy,     -   one or more halogens, or         a C₆ to C₈ aryl;         a C₂ to C₆ alkylene;         a C₆ to C₈ aryl optionally substituted with an alkoxy or one or         more C₁ to C₆ alkyls;         a —COOR_(x) group, where R_(x) is as defined above; or

R is a hydrogen, a halogen or an alkoxy;

R₁ is:

a hydrogen; a hydroxy; a halogen; a haloalkyl; a nitro group; a 5 or 6 membered heteroaryl; a 5 or 6 membered heterocycle; an alkoxy optionally substituted with:

-   -   one or more halogens,     -   a C₆ to C₈ aryl, or     -   a 5 or 6 membered heterocycle;         a C₆ to C₈ aryl optionally substituted with an alkoxy;         a —COR_(x) group, where R_(x) is as defined above;         a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or         a 5 or 6 membered heterocycle; or         R₁ joins together with R₂ to form:

R₂ is:

a nitro group; a hydrogen; a halogen; a hydroxy group; a C₁ to C₆ alkyl group, optionally substituted with one or more halogens; an amino group; an alkoxy group optionally substituted with:

-   -   one or more halogens,     -   an —OCOR_(x) group, where R_(x) is as defined above,     -   a dialkyl-amino optionally substituted with an alkoxy,     -   a 5 or 6 membered heterocycle group optionally substituted with         a C₁ to C₆ alkyl,     -   a 5 or 6 membered heteroaryl group, or     -   a C₆ to C₈ aryl group;         a —COOR_(x) group, where R_(x) is as defined above;         a haloalkyl;         an amide group optionally substituted with:     -   a hydroxy group, or     -   a C₆ to C₈ aryl;         a 5 or 6 membered heteroaryl;         a —OCOR_(x) group, where R_(x) is as defined above;         a —NHCOR_(jj) group, where R_(jj) is:     -   an alkoxy, or     -   an amino optionally substituted with one or more C₁ to C₆         alkyls;         a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;         a —NHSO₂R_(x) group, where R_(x) is as defined above; or         R₂ joins together with R₁ to form:

R₃ is:

a hydrogen; or —CH₂OCOR_(x), and R_(x) is as defined above; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and optionally one or more compound known in the art to affect IRES activity. Embodiment 32. The method of Embodiment 31, wherein said compound known in the art to affect IRES activity affects IRES mediated translation of the single ORF encoding the polyprotein. Embodiment 33. A pharmaceutical composition for affecting viral IRES activity in a subject infected with a virus, comprising one or more compound having the following formula, in an amount effective for affecting viral IRES activity:

wherein:

X is:

hydrogen; a nitro group; a cyano group; a —COR_(a) group, where R_(a) is:

-   -   a C₁ to C₆ alkyl,     -   a C₆ to C₈ aryl optionally substituted with an alkoxy or a         halogen, or     -   a dialkyl-amino;         a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;         a formyl group;         a C₆ to C₈ aryl optionally substituted with an alkoxy; or         a 5 or 6-membered heteroaryl optionally substituted with:     -   a C₁ to C₆ alkyl,     -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or         more halogens, or     -   a 5 to 6 membered heteroaryl;

Y is:

a hydrogen; a haloalkyl; a halogen; an amino optionally substituted with one or more C₁ to C₆ alkyls; a benzofuran; a benzothiophene; a dibenzofuran; a dibenzothiophene; a benzothiazole; a naphthalene; an indole, optionally substituted on the nitrogen with a C₁ to C₆ alkyl;

where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined above, or an —SO₂R_(x), where R_(x) is as defined above; or

where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl; a —NHCOR_(e) group, where R_(e) is:

-   -   a C₁ to C₆ alkyl;     -   a C₆ to C₈ aryl optionally substituted with:         -   a C₁ to C₆ alkyl,         -   an alkoxy,         -   a cyano group,         -   a nitro group, or         -   a halogen;             a —NHCOOR_(x) group, where R_(x) is as defined above;             a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;             a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a             hydrogen and R_(h) is a C₆ to C₈ aryl optionally substituted             with an alkoxy;             a C₁ to C₆ alkyl;             a 5 or 6 membered heteroaryl, optionally substituted with:     -   a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈ aryl,     -   a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where         R_(x) is as defined above, or     -   an amino group;         a 5 or 6 membered heterocycle optionally substituted with:     -   a —COOR_(x) group, where R_(x) is as defined above, or     -   a —NHCOOR_(x) group, where R_(x) is as defined above;         a C₆ to C₈ aryl, optionally substituted with one or more of the         following:     -   an alkoxy, optionally substituted with:         -   an alkoxy,         -   a hydroxy,         -   one or more halogens,         -   a 5 or 6 membered heterocycle, optionally substituted with:             -   a C₁ to C₆ alkyl, or             -   a hydroxy,         -   an amino group optionally substituted with one or more C₁ to             C₆ alkyls,         -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and             R_(i) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a haloalkyl, or             -   a haloalkoxy,         -   a —NR_(j)COR_(k) group, where R_(k) is:             -   a C₁ to C₆ alkyl,             -   a hydrogen, or             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls,         -   and R_(j) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a haloalkyl, or             -   a haloalkoxy,         -   a —N═N⁺═N⁻ group, or         -   a —COR_(l), where R_(l) is a 5 or 6 membered heterocycle             optionally substituted with a hydroxy,     -   an amino optionally substituted with one or more C₁ to C₆         alkyls,     -   a nitro group,     -   a C₁ to C₆ alkyl group, optionally substituted with:         -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or         -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,     -   a haloalkoxy,     -   a halogen,     -   a hydroxy,     -   a —COOR_(x) group, where R_(x) is as defined above,     -   a —COR_(m) group, where R_(m) is:         -   an amino optionally substituted with one or more C₁ to C₆             alkyls, where the C₁ to C₆ alkyls are optionally substituted             with:             -   a hydroxy             -   a 5 or 6 membered heterocycle,             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls,             -   an alkoxy,         -   a3 to 7 membered heterocycle, optionally substituted with a             C₁ to C₆ alkyl, optionally substituted with a dialkyl-amino,         -   a —NHR_(n) group, where R_(n) is:             -   a —CH₂CONH₂, or             -   a C₆ to C₈ aryl optionally substituted with:                 -   an alkyl,                 -   one or more halogens,                 -   a nitro group, or                 -   one or more alkoxys,     -   a —NR_(o)COR_(p) group, where R_(p) is:         -   a C₁ to C₆ alkyl optionally substituted with:             -   a halogen,             -   an alkoxy, or             -   a C₆ to C₈ aryl,         -   a 5 or 6 membered heterocycle,         -   a C₆ to C₈ aryl, optionally substituted with a halogen,         -   a 5 or 6 membered heteroaryl optionally substituted with one             or more C₁ to C₆ alkyls,         -   a hydrogen,

-   -   and where R_(o) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl, or         -   a haloalkoxy,     -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a haloalkyl,         -   a haloalkoxy, or         -   a —COR_(x) group, where R_(x) is as defined above,     -   and where R_(r) is:         -   a C₆ to C₈ aryl optionally substituted with:

-   -   -   -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or             -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a C₁ to C₆ alkyl optionally substituted with one or more of             the following:             -   a halogen,             -   an alkylene,             -   a C₆ to C₈ aryl, or             -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a —COOR_(x) group, where R_(x) is as defined above,

    -   a —NR_(t)COOR_(u) group, where R_(u) is:         -   a C₁ to C₁₂ alkyl, optionally substituted with:             -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆                 alkyl or an alkoxy,             -   an alkylene,             -   an alkoxy,             -   an alkyne,             -   a halogen, or             -   a 5 or 6 membered heterocycle,         -   a C₆ to C₈ aryl, optionally substituted with:             -   an alkoxy,             -   a halogen, or             -   a C₁ to C₆ alkyl, or         -   a 5 or 6 membered heterocycle,

    -   and R_(t) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl, or         -   a haloalkoxy,

    -   a —NR_(v)SO₂R_(w) group, where R_(v) is:         -   a hydrogen,         -   a —COR_(x), where R_(x) is as defined above, or         -   a C₁ to C₆ alkyl, optionally substituted with:             -   a halogen,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a —OCOR_(x) group, where is as defined above,             -   a hydroxyl,             -   a hydroxyl, or             -   an alkoxy,

    -   and where R_(w) is:         -   a C₁ to C₆ alkyl optionally substituted with:             -   a halogen,             -   a haloalkyl,             -   a C₆ to C₈ aryl, or             -   a 5 or 6 membered heterocycle,         -   a C₂ to C₆ alkylene,         -   an alkyl- or dialkyl-amino optionally substituted with a             halogen,         -   a 5 or 6 membered heterocycle, or         -   a 5 or 6 membered heteroaryl optionally substituted with:             -   a C₁ to C₆ alkyl,             -   a 5 or 6 membered heterocycle, or

optionally substituted with a C₁ to C₆ alkyl, where R_(y) is a C₁ to C₆ alkyl or hydrogen,

-   -   where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally         substituted with a C₆ to C₈ aryl,     -   a —SR_(x) group, where R_(x) is as defined above,     -   a —SO₂R_(aa) group, where R_(aa) is:         -   a C₁ to C₆ alkyl,         -   an amino group,         -   an alkyl- or dialkyl-amino group optionally substituted with             a hydroxy or a —COOR_(x) group, where R_(x) is as defined             above,         -   a 5 or 6 membered heteroaryl,     -   a C₆ to C₈ aryl, or     -   a —NHR_(bb) group, where R_(bb) is:

-   -   -   a —C(═S)NH₂ group, or

    -   a —PO(OR_(x))₂, where R_(x) is as defined above;

group, where R_(cc) is:

-   -   a naphthalene,     -   a 5 or 6 membered heteroaryl,

-   -   a C₆ to C₈ aryl, optionally substituted with one or more of the         following:         -   an alkoxy,         -   an hydroxy,         -   a halogen,         -   a C₁ to C₆ alkyl, optionally substituted with a cyano group,         -   an amino optionally substituted with one or more C₁ to C₆             alkyls,         -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,         -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen             or a C₁ to C₆ alkyl, optionally substituted with a halogen,             and R_(ff) is:             -   a hydrogen,             -   a haloalkyl,             -   a haloalkoxy,             -   a C₁ to C₆ alkyl, or             -   a —COR_(x), where R_(x) is as defined above,         -   a —NR_(gg)COR_(hh) group, where R_(hh) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl optionally substituted with:                 -   an alkoxy,                 -   a halogen, or                 -   an amino optionally substituted with one or more C₁                     to C₆ alkyls,             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls, where the alkyls are optionally substituted                 with a halogen,             -   a 5 or 6 membered heterocycle,             -   a 5 or 6 membered heteroaryl,         -   and R_(gg) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a haloalkoxy, or             -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl,         -   5 or 6 membered heterocycle groups,         -   an amino optionally substituted with one or more C₁ to C₆             alkyls,         -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined above,             and R_(ii) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a haloalkoxy,             -   a —COR_(x) group, where R_(x) is as defined above;

Z is:

a hydrogen; a C₁ to C₆ alkyl optionally substituted with:

-   -   an alkoxy,     -   one or more halogens, or     -   a C₆ to C₈ aryl;         a C₂ to C₆ alkylene;         a C₆ to C₈ aryl optionally substituted with an alkoxy or one or         more C₁ to C₆ alkyls;         a —COOR_(x) group, where R_(x) is as defined above; or

R is a hydrogen, a halogen or an alkoxy;

R₁ is:

a hydrogen; a hydroxy; a halogen; a haloalkyl; a nitro group; a 5 or 6 membered heteroaryl; a 5 or 6 membered heterocycle; an alkoxy optionally substituted with:

-   -   one or more halogens,     -   a C₆ to C₈ aryl, or     -   a 5 or 6 membered heterocycle;         a C₆ to C₈ aryl optionally substituted with an alkoxy;         a —COR_(x) group, where R_(x) is as defined above;         a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or         a 5 or 6 membered heterocycle; or         R₁ joins together with R₂ to form:

R₂ is:

a nitro group; a hydrogen; a halogen; a hydroxy group; a C₁ to C₆ alkyl group, optionally substituted with one or more halogens; an amino group; an alkoxy group optionally substituted with:

-   -   one or more halogens,     -   an —OCOR_(x) group, where R_(x) is as defined above,     -   a dialkyl-amino optionally substituted with an alkoxy,     -   a 5 or 6 membered heterocycle group optionally substituted with         a C₁ to C₆ alkyl,     -   a 5 or 6 membered heteroaryl group, or     -   a C₆ to C₈ aryl group;         a —COOR_(x) group, where R_(x) is as defined above;         a haloalkyl;         an amide group optionally substituted with:     -   a hydroxy group, or     -   a C₆ to C₈ aryl;         a 5 or 6 membered heteroaryl;         a —OCOR_(x) group, where R_(x) is as defined above;         a —NHCOR_(jj) group, where R_(jj) is:     -   an alkoxy, or     -   an amino optionally substituted with one or more C₁ to C₆         alkyls;         a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;         a —NHSO₂R_(x) group, where R_(x) is as defined above; or         R₂ joins together with R₁ to form:

R₃ is:

a hydrogen; or —CH₂OCOR_(x), and R_(x) is as defined above; or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates the HCV-PV chimera construct. The cloverleaf-like RNA structure of PV, an essential cis-acting replication signal ending with the genome-linked protein VPg, is located at the 5′ end of the genome. The solid (HCV) and open (PV) boxes depict open reading frames encoding viral polypeptides. The position of the HCV core fragment (the first 123 amino acids) gene is denoted by Δ Core. Overall, the HCV_specific sequence in the HCV-PV spans from nucleotides 18 to 710 (139).

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, compounds that modify HCV translation have been identified and methods of using these compounds for preventing or treating HCV infection are provided. Without being limited to one theory, it is believed that the compounds of the present invention inhibit IRES-mediated initiation and translation. The HCV IRES directs the translation of a single long ORF encoding a polyprotein that is posttranslationally processed into at least 10 mature viral proteins, including the structural proteins core (putative nucleocapsid), E1 and E2 and the nonstructural (NS) proteins NS2 to NS5B.

A. Compounds of the Invention

In one aspect of the invention, compounds of the invention are provided which are useful for preventing or treating HCV infection.

Preferred compounds of the present invention useful for preventing or treating HCV infection include those of Formula (I) as shown below.

wherein:

X is:

hydrogen; a nitro group; a cyano group; a —COR_(a) group, where R_(a) is:

-   -   a C₁ to C₆ alkyl,     -   a C₆ to C₈ aryl optionally substituted with an alkoxy or a         halogen, or     -   a dialkyl-amino;         a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;         a formyl group;         a C₆ to C₈ aryl optionally substituted with an alkoxy; or         a 5 or 6-membered heteroaryl optionally substituted with:     -   a C₁ to C₆ alkyl,     -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or         more halogens, or     -   a 5 to 6 membered heteroaryl;

Y is:

a hydrogen; a haloalkyl; a halogen; an amino optionally substituted with one or more C₁ to C₆ alkyls; a benzofuran; a benzothiophene; a dibenzofuran; a dibenzothiophene; a benzothiazole; a naphthalene; an indole, optionally substituted on the nitrogen with a C₁ to C₆ alkyl;

where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as defined above, or an —SO₂R_(x), where R_(x) is as defined above; or

where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl; a —NHCOR_(e) group, where R_(e) is:

-   -   a C₁ to C₆ alkyl;     -   a C₆ to C₈ aryl optionally substituted with:         -   a C₁ to C₆ alkyl,         -   an alkoxy,         -   a cyano group,         -   a nitro group, or         -   a halogen;             a —NHCOOR_(x) group, where R_(x) is as defined above;             a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;             a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a             hydrogen and R_(h) is a C₆ to C₈ aryl optionally substituted             with an alkoxy;             a C₁ to C₆ alkyl;             a 5 or 6 membered heteroaryl, optionally substituted with:     -   a C₁ to C₆ alkyl, optionally substituted with a C₆ to C_(g)         aryl,     -   a C₆ to C₈ aryl, optionally substituted with —COOR_(x), where         R_(x) is as defined above, or     -   an amino group;         a 5 or 6 membered heterocycle optionally substituted with:     -   a —COOR_(x) group, where R_(x) is as defined above, or     -   a —NHCOOR_(x) group, where R_(x) is as defined above;         a C₆ to C₈ aryl, optionally substituted with one or more of the         following:     -   an alkoxy, optionally substituted with:         -   an alkoxy,         -   a hydroxy,         -   one or more halogens,         -   a 5 or 6 membered heterocycle, optionally substituted with:             -   a C₁ to C₆ alkyl, or             -   a hydroxy,         -   an amino group optionally substituted with one or more C₁ to             C₆ alkyls,         -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above and             R_(i) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a haloalkyl, or             -   a haloalkoxy,         -   a —NR_(j)COR_(k) group, where R_(k) is:             -   a C₁ to C₆ alkyl,             -   a hydrogen, or             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls,         -   and R_(j) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a haloalkyl, or             -   a haloalkoxy,         -   a —N═N⁺═N⁻ group, or         -   a —COR_(l), where R_(l) is a 5 or 6 membered heterocycle             optionally substituted with a hydroxy,     -   an amino optionally substituted with one or more C₁ to C₆         alkyls,     -   a nitro group,     -   a C₁ to C₆ alkyl group, optionally substituted with:         -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or         -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined above,     -   a haloalkoxy,     -   a halogen,     -   a hydroxy,     -   a —COOR_(x) group, where R_(x) is as defined above,     -   a —COR_(m) group, where R_(m) is:         -   an amino optionally substituted with one or more C₁ to C₆             alkyls, where the C₁ to C₆ alkyls are optionally substituted             with:             -   a hydroxy             -   a 5 or 6 membered heterocycle,             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls,             -   an alkoxy,         -   a3 to 7 membered heterocycle, optionally substituted with a             C₁ to C₆ alkyl, optionally substituted with a dialkyl-amino,         -   a —NHR_(n) group, where R_(n) is:             -   a —CH₂CONH₂, or             -   a C₆ to C₈ aryl optionally substituted with:                 -   an alkyl,                 -   one or more halogens,                 -   a nitro group, or                 -   one or more alkoxys,     -   a —NR_(o)COR_(p) group, where R_(p) is:         -   a C₁ to C₆ alkyl optionally substituted with:             -   a halogen,             -   an alkoxy, or             -   a C₆ to C₈ aryl,         -   a 5 or 6 membered heterocycle,         -   a C₆ to C₈ aryl, optionally substituted with a halogen,         -   a 5 or 6 membered heteroaryl optionally substituted with one             or more C₁ to C₆ alkyls,         -   a hydrogen,

-   -   and where R_(o) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl, or         -   a haloalkoxy,     -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a haloalkyl,         -   a haloalkoxy, or         -   a —COR_(x) group, where R_(x) is as defined above,     -   and where R₁ is:         -   a C₆ to C₈ aryl optionally substituted with:

-   -   -   -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or             -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a C₁ to C₆ alkyl optionally substituted with one or more of             the following:             -   a halogen,             -   an alkylene,             -   a C₆ to C₈ aryl, or             -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a —COOR_(x) group, where R_(x) is as defined above,

    -   a —NR_(t)COOR_(u) group, where R_(u) is:         -   a C₁ to C₁₂ alkyl, optionally substituted with:             -   a C₆ to C₈ aryl optionally substituted with a C₁ to C₆                 alkyl or an alkoxy,             -   an alkylene,             -   an alkoxy,             -   an alkyne,             -   a halogen, or             -   a 5 or 6 membered heterocycle,         -   a C₆ to C₈ aryl, optionally substituted with:             -   an alkoxy,             -   a halogen, or             -   a C₁ to C₆ alkyl, or         -   a 5 or 6 membered heterocycle,

    -   and R_(t) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,         -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl, or         -   a haloalkoxy,

    -   a —NR_(v)SO₂R_(w) group, where R_(v) is:         -   a hydrogen,         -   a —COR_(x), where R_(x) is as defined above, or         -   a C₁ to C₆ alkyl, optionally substituted with:             -   a halogen,             -   a —COR_(x) group, where R_(x) is as defined above,             -   a —OCOR_(x) group, where R_(x) is as defined above,             -   a hydroxyl,             -   a hydroxyl, or             -   an alkoxy,

    -   and where R_(w) is:         -   a C₁ to C₆ alkyl optionally substituted with:             -   a halogen,             -   a haloalkyl,             -   a C₆ to C₈ aryl, or             -   a 5 or 6 membered heterocycle,         -   a C₂ to C₆ alkylene,         -   an alkyl- or dialkyl-amino optionally substituted with a             halogen,         -   a 5 or 6 membered heterocycle, or         -   a 5 or 6 membered heteroaryl optionally substituted with:             -   a C₁ to C₆ alkyl,             -   a 5 or 6 membered heterocycle, or

optionally substituted with a C₁ to C₆ alkyl, where R_(y) is a C₁ to C₆ alkyl or hydrogen,

-   -   where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally         substituted with a C₆ to C₈ aryl,     -   a —SR_(x) group, where R_(x) is as defined above,     -   a —SO₂R_(aa) group, where R_(aa) is:         -   a C₁ to C₆ alkyl,         -   an amino group,         -   an alkyl- or dialkyl-amino group optionally substituted with             a hydroxy or a —COOR_(x) group, where R_(x) is as defined             above,         -   a 5 or 6 membered heteroaryl,     -   a C₆ to C₈ aryl, or     -   a —NHR_(bb) group, where R_(bb) is:

-   -   -   a —C(═S)NH₂ group, or         -   a —PO(OR_(x))₂, where R_(x) is as defined above;

group, where R_(cc) is:

-   -   a naphthalene,     -   a 5 or 6 membered heteroaryl,

-   -   a C₆ to C₈ aryl, optionally substituted with one or more of the         following:         -   an alkoxy,         -   an hydroxy,         -   a halogen,         -   a C₁ to C₆ alkyl, optionally substituted with a cyano group,         -   an amino optionally substituted with one or more C₁ to C₆             alkyls,         -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,         -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a hydrogen             or a C₁ to C₆ alkyl, optionally substituted with a halogen,             and R_(ff) is:             -   a hydrogen,             -   a haloalkyl,             -   a haloalkoxy,             -   a C₁ to C₆ alkyl, or             -   a —COR_(x), where R_(x) is as defined above,         -   a —NR_(gg)COR_(hh) group, where R_(hh) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl optionally substituted with:                 -   an alkoxy,                 -   a halogen, or                 -   an amino optionally substituted with one or more C₁                     to C₆ alkyls,             -   an amino optionally substituted with one or more C₁ to                 C₆ alkyls, where the alkyls are optionally substituted                 with a halogen,             -   a 5 or 6 membered heterocycle,             -   a 5 or 6 membered heteroaryl,         -   and R_(gg) is:             -   a hydrogen,             -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a haloalkoxy, or             -   a —COR_(x) group, where R_(x) is as defined above,         -   a haloalkyl,         -   5 or 6 membered heterocycle groups,         -   an amino optionally substituted with one or more C₁ to C₆             alkyls,         -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined above,             and R_(ii) is:         -   a hydrogen,         -   a C₁ to C₆ alkyl,             -   a haloalkyl,             -   a haloalkoxy,             -   a —COR_(x) group, where R_(x) is as defined above;

Z is:

a hydrogen; a C₁ to C₆ alkyl optionally substituted with:

-   -   an alkoxy,     -   one or more halogens, or     -   a C₆ to C₈ aryl;         a C₂ to C₆ alkylene;         a C₆ to C₈ aryl optionally substituted with an alkoxy or one or         more C₁ to C₆ alkyls;         a —COOR_(x) group, where R_(x) is as defined above; or

R is a hydrogen, a halogen or an alkoxy;

R₁ is:

a hydrogen; a hydroxy; a halogen; a haloalkyl; a nitro group; a 5 or 6 membered heteroaryl; a 5 or 6 membered heterocycle; an alkoxy optionally substituted with:

-   -   one or more halogens,     -   a C₆ to C₈ aryl, or     -   a 5 or 6 membered heterocycle;         a C₆ to C₈ aryl optionally substituted with an alkoxy;         a —COR_(x) group, where R_(x) is as defined above;         a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or         a 5 or 6 membered heterocycle; or         R₁ joins together with R₂ to form:

R₂ is:

a nitro group; a hydrogen; a halogen; a hydroxy group; a C₁ to C₆ alkyl group, optionally substituted with one or more halogens; an amino group; an alkoxy group optionally substituted with:

-   -   one or more halogens,     -   an —OCOR_(x) group, where R_(x) is as defined above,     -   a dialkyl-amino optionally substituted with an alkoxy,     -   a 5 or 6 membered heterocycle group optionally substituted with         a C₁ to C₆ alkyl,     -   a 5 or 6 membered heteroaryl group, or     -   a C₆ to C₈ aryl group;         a —COOR_(x) group, where R_(x) is as defined above;         a haloalkyl;         an amide group optionally substituted with:     -   a hydroxy group, or     -   a C₆ to C₈ aryl;         a 5 or 6 membered heteroaryl;         a —OCOR_(x) group, where R_(x) is as defined above;         a —NHCOR_(jj) group, where R_(jj) is:     -   an alkoxy, or     -   an amino optionally substituted with one or more C₁ to C₆         alkyls;         a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;         a —NHSO₂R_(x) group, where R_(x) is as defined above; or         R₂ joins together with R₁ to form:

R₃ is:

a hydrogen; or —CH₂OCOR_(x), and R_(x) is as defined above; or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, a compound or a composition of the present invention includes a compound of Formula I, wherein the compound of Formula I is not

As used herein, the term “alkyl” generally refers to saturated hydrocarbyl radicals of straight or branched configuration, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, octyl, n-octyl, and the like. In some embodiments, alkyl substituents may be C₁ to C₁₂, or C₁ to C₈ or C₁ to C₆ alkyl groups.

As used herein, “alkylene” generally refers to linear, branched or cyclic alkene radicals having one or more carbon-carbon double bonds, such as C₂ to C₆ alkylene groups including 3-propenyl.

As used herein, “aryl” refers to a carbocyclic aromatic ring structure. Included in the scope of aryl groups are aromatic rings having from five to twenty carbon atoms. Aryl ring structures include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. Examples of aryl groups that include phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl (i.e., phenanthrene), and naphtyl (i.e., naphthalene) ring structures. In certain embodiments, the aryl group may be optionally substituted.

As used herein, “heteroaryl” refers to cyclic aromatic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S or N atoms. Included within the scope of heteroaryl, and independently selectable, are O, N, and S heteroaryl ring structures. The ring structure may include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. In some embodiments, the heteroaryl groups may be selected from heteroaryl groups that contain two or more heteroatoms, three or more heteroatoms, or four or more heteroatoms. Heteroaryl ring structures may be selected from those that contain five or more atoms, six or more atoms, or eight or more atoms. Examples of heteroaryl ring structures include: acridine, benzimidazole, benzoxazole, benzodioxole, benzofuran, 1,3-diazine, 1,2-diazine, 1,2-diazole, 1,4-diazanaphthalene, furan, furazan, imidazole, indole, isoxazole, isoquinoline, isothiazole, oxazole, purine, pyridazine, pyrazole, pyridine, pyrazine, pyrimidine, pyrrole, quinoline, quinoxaline, thiazole, thiophene, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, tetrazole and quinazoline.

As used herein, “heterocycle” refers to cyclic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S or N atoms. Included within the scope of heterocycle, and independently selectable, are O, N, and S heterocycle ring structures. The ring structure may include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. Example of heterocyclo groups include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl or tetrahydrothiopyranyl and the like. In certain embodiments, the heterocycle may optionally be substituted.

As used herein, “alkoxy” generally refers to a group with the structure —O—R, where R is an alkyl group as defined above.

For the purposes of this invention, halo substituents may be independently selected from the halogens such as fluorine, chlorine, bromine, iodine, and astatine. A haloalkyl is an alkyl group, as defined above, substituted with one or more halogens. A haloalkoxy is an alkoxy group, as defined above, substituted with one or more halogens.

For the purposes of this invention, where one or more functionalities encompassing X, Y, Z, R, R₁, R₂, and R₃, are incorporated into a molecule of Formula (I), each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently substituted. Further, where a more generic substituent is set forth for any position in the molecules of the present invention, it is understood that the generic substituent may be replaced with more specific substituents, and the resulting molecules are within the scope of the molecules of the present invention.

By “substituted” or “optionally substituted” it is meant that the particular substituent may be substituted with a chemical group known to one of skill in the art to be appropriate for the referred-to substituent, unless a chemical group is specifically mentioned.

Exemplary X substituents include the following, where the * indicates the bond of attachment of the scaffold molecule.

Preferred X substituents include -hydrogen; -a cyano group; and -a —COR_(a) group, where R_(a) is: -a C₁ to C₆ alkyl, or -a dialkyl-amino.

Preferred X substituents also include the following, where the * indicates the bond of attachment of the scaffold molecule.

More preferred X substituents include the following, where the * indicates the bond of attachment of the scaffold molecule.

Exemplary Y substituents include the following, where the * indicates the bond of attachment of the scaffold molecule.

Preferred Y substituents include the following, where the * indicates the bond of attachment of the scaffold molecule.

More preferred Y substituents include the following, where the * indicates the bond of attachment of the scaffold molecule.

Exemplary Z substituents include the following, where the * indicates the bond of attachment of the scaffold molecule.

Preferred Z substituents include -a hydrogen; -a C₁ to C₆ alkyl optionally substituted with: -an alkoxy, -one or more halogens, or -a C₆ to C₈ aryl; -a C₂ to C₆ alkylene; and -a C₆ to C₈ aryl optionally substituted with an alkoxy.

Preferred Z substituents also include the following, where the * indicates the bond of attachment of the scaffold molecule.

More preferred Z substituents include -a hydrogen; -a C₁ to C₆ alkyl optionally substituted with: -a C₆ to C₈ aryl; -a C₂ to C₆ alkylene; and -a C₆ to C₈ aryl optionally substituted with an alkoxy.

More preferred Z substituents include the following, where the * indicates the bond of attachment of the scaffold molecule.

Exemplary R substituents include the following:

Preferred R substituents include the following:

*—H

Exemplary R₁ substituents include the following:

Preferred R₁ substituents include -a hydrogen; -a halogen; -a nitro group; -a 5 or 6 membered heterocycle; -an alkoxy optionally substituted with: -a C₆ to C₈ aryl; -a C₆ to C₈ aryl optionally substituted with an alkoxy.

Preferred R₁ substituents also include the following:

More preferred R₁ substituents include the following:

Exemplary R₂ substituents include the following:

Preferred R₂ substituents include -a nitro group; -a hydrogen; -a halogen; -a hydroxy group; -a C₁ to C₆ alkyl group, optionally substituted with one or more halogens; -an alkoxy group optionally substituted with: -one or more halogens, -an —OCOR_(x) group, where R_(x) is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C₁ to C₆ alkyl, or -a 5 or 6 membered heteroaryl group; -an amide group; and -a —NHSO₂R_(x) group, where R_(x) is as defined above.

Preferred R₂ substituents also include the following:

More preferred R₂ substituents include -a hydrogen; -a C₁ to C₆ alkyl group, optionally substituted with one or more halogens; -an alkoxy group optionally substituted with: -one or more halogens, -a 5 or 6 membered heterocycle group optionally substituted with a C₁ to C₆ alkyl, or -a 5 or 6 membered heteroaryl group.

More preferred R₂ substituents also include the following:

Exemplary R₃ substituents include the following:

Preferred R₃ substituents include the following:

*—H

Compounds of the invention include the following:

The above compounds were prepared using the schemes and examples set forth below. Other methods of producing these compounds are known to one of skill in the art.

Preferred compounds include the following compounds in Table A:

TABLE A

  22

  23

  26

  48

  53

  69

  81

  82

  83

  84

  85

  86

  87

  88

  94

  95

  96

  119

  130

  131

  132

  134

  138

  139

  144

  145

  153

  157

  161

  166

  169

  172

  173

  175

  176

  180

  181

  182

  185

  188

  196

  200

  201

  204

  205

  206

  207

  211

  213

  214

  216

  217

  218

  219

  220

  221

  223

  233

  243

  251

  252

  264

  266

  269

  294

  295

  296

  297

  298

  299

  301

  302

  304

  306

  309

  310

  331

  341

  345

  346

  349

  350

  351

  353

  365

  366

  367

  369

  394

  396

  397

  398

  399

  401

  403

  405

  406

  408

  413

  415

  416

  417

  418

  420

  422

  430

  440

  441

  445

  447

  456

  461

  462

  468

  469

  470

  471

  472

  473

  475

  477

  478

  480

  487

  488

  490

  492

  493

  495

  498

  499

  516

  518

  519

  520

  521

  522

  523

  524

  525

  526

  528

  530

  531

  532

  533

  534

  535

  536

  537

  538

  539

  542

  543

  544

  545

  546

  547

  548

  549

  550

  551

  552

  557

  562

  563

  567

  570

  580

  581

  582

  585

  596

  601

  602

  606

  607

  611

  612

  613

  614

  616

  617

  618

  619

  621

  622

  623

  625

  626

  627

  628

  631

  633

  635

  636

  637

  641

  650

  652

  661

  662

  666

  667

  669

  670

  671

  672

  676

  677

  679

  680

  681

  687

  690

  691

  692

  693

  697

  698

  699

  701

  702

  706

  707

  709

  713

  715

  716

  717

  720

  723

  724

  725

  726

  727

  728

  730

  731

  732

  734

  735

  736

  737

  738

  741

  742

  743

  744

  745

  747

  748

  749

  750

  751

  752

  753

  755

  756

  757

  758

  759

  760

  761

  762

  763

  764

  767

  771

  772

  774

  775

  776

  777

  778

  779

  780

  781

  784

  789

  790

  791

  792

  793

  794

  795

  799

  801

  802

  807

  813

  818

  822

  827

  834

  835

  848

  850

  851

  853

  854

  855

  858

  859

  861

  863

More preferred compounds include the following compounds in Table B:

TABLE B

22

23

81

83

84

85

86

87

130

131

166

180

182

204

214

217

243

252

294

346

349

353

365

366

369

394

396

397

398

399

401

406

413

415

416

417

418

447

461

462

468

470

471

472

473

475

477

478

480

488

493

495

499

518

519

520

521

522

523

524

526

528

530

534

535

537

539

544

546

547

549

552

562

580

601

602

606

607

611

613

614

616

617

618

625

627

628

635

637

652

661

662

666

667

669

670

671

672

680

687

692

697

699

706

709

713

715

716

720

726

728

730

731

735

736

738

741

743

744

745

747

748

749

750

751

753

755

756

757

758

759

760

761

762

763

764

767

771

772

774

776

777

778

779

781

789

790

791

792

793

794

795

799

801

802

807

813

818

827

853

858

863

B. Preparation of Compounds of the Invention

Indole compounds of the present invention can be obtained via standard, well-known synthetic methodology. Many of the indole starting materials can be prepared the routes described below or by those skilled in the art.

Compounds of formula I, represented by structure II can be prepared by the methodology depicted in Scheme A below:

An α-nitroketone derivative A2 can be derived from treatment of the anion of nitromethane, obtained from the treatment of nitromethane with a base, such as, e.g., sodium or potassium t-butoxide or sodium hydride, with an activated carboxylic acid derivative, e.g., the acyl imidazolide A1. Reaction of the α-nitroketone A2 with amine derivative A3 can afford the nitro enamine A4 by mixing the components A3 and A4 and heating in a suitable solvent such as an alcohol or an aprotic solvent. Treatment of the nitro enamine A4 with quinone A5 in a polar protic solvent such as acetic acid at or near ambient temerature gives the compound of formula II.

Compounds of formula I, represented by structure III can be prepared as shown in Scheme B below:

Treatment of B1 with a reactive alkyl or aryl group containing a leaving group L in a suitable solvent, with or without heat in the presence of a base, such an inorganic base, e.g., sodium or potassium carbonate or an organic base, e.g., triethylamine, can afford the compound of structure III. Examples of leaving groups include but are not limited to halogens (e.g., chlorine, bromine or iodine) or alkyl or arylsulfonates.

Compounds of formula I, represented by structure IV can be prepared as shown in Scheme C below:

Compounds of structure IV can be obtained by nitrating an indole of structure C1, to give the 3-nitroindole C2. The nitration can be carried out by treatment of C1 with a nitrating agent, such as nitric acid or sodium nitrite in a solvent such as acetic acid, acetic anhydride, sulfuric acid or in a mixed solvent system containing an organic solvent such as dichloromethane. The reaction can be carried out a temperature of −30° C. to +50° C. Treatment of C2 with a reactive functional group R₉ containing a suitable leaving group L (C3) can give compounds of structure IV. Reactive functional groups can consist of but are not limited to alkyl and aralkyl. L can represent a halide, particularly chloro, bromo or iodo or an alkylsulfonate. The reaction between C2 and C3 can be carried out in a suitable solvent in the presence of an inorganic base such as potassium carbonate or sodium hydride or an organic base such as a trialkylamine. Alternatively, the group R₉ can represent an aryl or heteroaryl group and L can represent a halide, particularly chloro, bromo or iodo. The reaction can be carried out in a polar or nonpolar solvent at a temperature from ambient to 200° C. in the presence of a copper catalyst, e.g., CuI, a base such as Cs₂CO₃ or K₃PO₄, and optionally an amine ligand such as 1,2-bis(methylamino)ethane or 1,2-cyclohexanediamine.

An alternative pathway is to convert C1 into C4 in similar fashion as described above and then carry out the nitration reaction to afford compounds of structure IV.

Compounds of formula I, represented by structure V can be prepared as shown in Scheme D.

Treatment of β-ketoesters of structure D1 with amines D2 gives the amino crotonate derivatives D3 by heating in a suitable solvent such as an alcohol or an aprotic solvent. Reaction between D3 and quinone D4 in a polar protic solvent, such as acetic acid gives compounds of structure V.

Compounds of the present invention, represented by structure VI compounds can be prepared by the chemistry described in scheme E below.

Indole-3-carboxylic esters E1 can be converted to indole-3-carboxylic acids E2 by treatment of compounds of structure E1 with, for example, either acid or base in aqueous or mixed aqueous-organic solvents at ambient or elevated temperature or by treatment with nucleophilic agents, for example, boron tribromide or trimethylsilyl iodide, in a suitable solvent. Compounds of type E2 can then be activated and treated with amines of type E3 to give compounds E4. Activation of the carboxylic acid can be carried out, for example, by any of the standard methods. For example, the acid E2 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of the amine E3, or alternatively the acid can be activated as the acid chloride by treatment of the acid with, e.g., thionyl chloride or oxalyl chloride or as the acyl imidazolide, obtained by treatment of the acid with carbonyl diimidazole, followed by treatment of the amine E3. Compounds E4 can be converted to compounds of structure VI by treatment of E4 with a reactive functional group R₉ containing a suitable leaving group L (E5) as described previously. Alternatively, compounds of type E1 can be converted to compounds of structure E6 by treatment with E5. Indole-3-carboxylic esters E6 can then be converted to indole-3-carboxylic acids E7 by the methods described above. Conversion of E7 to compounds of structure VI can be carried out by the activation and reaction with an amine E3 as described above.

Compounds of the present invention, represented by structure VII compounds can be prepared by the chemistry described in scheme F below.

Indoles F1 can be formylated with reagents such as phosphorous oxychloride in the presence of DMF to give the indole-3-carboxaldehydes F2. Conversion to compounds of structure VII can be accomplished by treatment of F2 with compounds F3 as described previously. Alternatively, compounds of type F1 can first be converted to F4 and then be formylated to compounds of structure VII.

Compounds of formula G, represented by structure VIII can be prepared as shown in Scheme G.

Indole-3-carboxaldehydes of structure G1 can be converted to the indole-3-carboxylicacid derivatives by oxidation with reagents such as potassium permanganate under aqueous conditions.

Compounds of formula H, represented by structure IX can be prepared as shown in Scheme H.

Indole-3-carboxaldehydes of structure H1 can be converted to the indole-3-carbonitrile derivatives H2 by a variety of methods. Treatment of H1 with a nitroalkane, e.g., nitropropane, in the presence of an amine source, e.g., ammonium hydrogen phosphate gives the indole-3-carbonitrile H2 derivative. An alternative pathway to compound H2 is via the intermediate H3. Conversion of H1 to the oxime derivative H3 can be followed by dehydration, e.g., treatment of the oxime with acetic anhydride and a base, or reaction of the oxime with thionyl chloride to give H2. The compound H2 can then be reacted with a reactive functional group R₉ containing a suitable leaving group L (H4) as described previously to afford compounds of structure IX.

Alternatively, H1 can be reacted with a reactive functional group R₉ containing a suitable leaving group L (H4) to give the intermediate H5 which can be reacted with a nitroalkane as above to give the indole-3-carbonitrile IX compound. Compound IX can also be obtained by conversion to the oxime H6 followed by a dehydration reaction as described above.

Compounds of the present invention, represented by structure X can also be prepared as described in scheme I below.

Indoles I1 can be cyanated with an appropriate cyanating agent, e.g., chlorosulfonyl isocyanate (I2) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g. DMF, CH₃CN or dioxane, to afford compounds of structure I3. The compound I3 can then be reacted with a reactive functional group R₉ containing a suitable leaving group L (I4) as described previously afford the compound X.

Alternatively, compound I1 can be reacted with a reactive functional group R₉ containing a suitable leaving group L to give compounds of structure I5 which can then be cyanated as above to give compounds of formula X.

Compounds of formula J, represented by structure XI can be prepared as shown in Scheme J.

Amino crotonates J1 can be reacted with amines J2 to give J3. Reaction of J3 with quinone in the presence of a polar, protic solvent, e.g., acetic acid, gives the compound of structure XI.

Compounds of the present invention, represented by structure XII and XIII can be prepared as described in scheme K below.

Aldehydes of structure K1 can be reacted with an alkyl azidoacetate K2 by heating the components together in a suitable organic solvent, e.g., a protic or non-protic solvent, in the presence of an organic or inorganic base, to give the α-azidoacrylate K3. Heating K3 in the presence of a suitable non-reactive organic solvent, e.g., toluene or xylenes can give the 2-alkoxycarbonylindoles K4. Reduction of the ester functionality with a suitable reducing reagent, for example, lithium aluminum hydride, in a suitable solvent, e.g., ether or THF can give the intermediate K5. Reaction of K5 with a reactive functional group R₉ containing a suitable leaving group L (K6) as described in previously affords the compound K7. Cyanation of K7 with a cyanating agent, e.g., chlorosulfonyl isocyanate as described previously can give compound XII. Alternatively, cyanation of K5 with chlorosulfonyl isocyanate gives K8, which can be reacted with a reactive functional group R₉ containing a suitable leaving group L (K6) as described previously, affords, the compound XII.

An alternative use of intermediate K4 is exemplified below. Hydrolysis of the 2-alkoxycarbonyl group of the indole K4 either under acidic or basic conditions followed by decarboxylation can give the intermediate K9. Decarboxylation can be carried out thermally, i.e., heating in an appropriate solvent, e.g., toluene, xylenes, or quinoline. Alternatively, a source of copper can be added, for example, copper bronze, to facilitate decarboxylation. Reaction of K9 with a reactive functional group R₉ containing a suitable leaving group L (K6) as described above can afford the compounds K10. Cyanation of K10 with a cyanating agent, e.g., chlorosulfonyl isocyanate as described previously can hive compound XIII. Alternatively, cyanation of K9 with chlorosulfonyl isocyanate gives K11, which can be reacted with a reactive functional group R₉ containing a suitable leaving group L (K6) as described in previously, affords the compound XIII.

Compounds of formula L, represented by structure XIV can be prepared as shown in Scheme L.

Compounds of formula L1 can be halogenated on the 2-methyl group to give 2-bromomethyl or chloromethyl indoles L2. The halogenation reaction can be conducted with reagents, e.g., N-bromo- or chlorosuccinimide. The reaction can be conducted in a suitable solvent, such as chloroform, carbon tetrachloride, or THF and carried out in a range between ambient temperature and 80° C. Optionally, a radical initiator may be added, e.g., benzoyl peroxide or AIBN. The compound L2 can then be reacted with a nucleophile R₅—W (L3) to give compounds of structure XIV. The reaction can be conducted in a suitable solvent, e.g., THF, CH₂Cl₂ or DMF, within a temperature range of 0° C. to 120° C. A base, e.g., an inorganic base, such as potassium carbonate or an organic base, such as a trialkylamine can be used to remove the acid formed in the reaction. The group W can refer to an N, O or S atom.

Compounds of the present invention, represented by structure XV can be prepared as described in scheme M below.

Anilines of structure M1 can be diazotized and the resulting diazonium salt can be reduced to give the phenyl hydrazine compound M2. Reaction between the hydrazine M2 and a ketone M3 under acidic conditions can give the indole compound M4. The conditions for the cyclization reaction can be carried out under typical conditions utilized by one skilled in the art, for example, acidic conditions, utilizing acids such as a Bronstead acid ,e.g., acetic acid, hydrochloric acid or polyphosphoric acid or a Lewis acid, e.g., zinc chloride. The reaction can be carried out in the presence of a co-solvent, e.g., CH₂Cl₂ or THF typically within a temperature range of 0° C. to 120° C. Reaction of M4 with a reactive functional group R₉ containing a suitable leaving group L (M5) as described previously, can afford compounds M6. Cyanation of the indole M6 with a cyanating agent such as chlorosulfonyl isocyanate can give the compound of structure XV.

Alternatively, the indole M4 can be cyanated to give compounds of structure M7. Reaction of M7 with a reactive functional group R₉ containing a suitable leaving group L (M5) as described above can give compounds of structure XV.

Compounds of formula I, represented by structure XVI can be prepared as shown in Scheme N.

Compounds of formula N1 can be reacted with a dialkylformamide dialkyl acetal, N2, e.g., dimethylformamide dimethyl acetal, optionally in the presence of a suitable solvent, e.g., DMF or dioxane, at a temperature range from ambient to 150° C. to give the compound of structure N3. Reduction of the nitro group of compounds of type N3 under standard conditions can give the indole compounds of structure N4. The reduction can be carried out via hydrogenation, using a sub-stoichiometric amount of a hydrogenation catalyst, e.g., platinum or palladium, in the presence of a hydrogen source in a protic or aprotic solvent. The reduction can be carried out in a temperature range of ambient to 80° C. Alternatively, the reduction can be carried out via chemical reduction, e.g., in the presence of stoichiometric amounts of Fe or Sn compounds in a suitable solvent at a temperature range of ambient to 100° C. The compound N4 can then be reacted with a reactive functional group R₉ containing a suitable leaving group L (N5) as described previously to afford compounds of structure N6. Cyanation of N6 with a cyanating agent such as chlorosulfonyl isocyanate in a suitable solvent can give the compounds of structure XVI.

Alternatively, compounds of structure N4 can be cyanated to give compounds of structure N7. Reaction with N7 with a reactive functional group R₉ containing a suitable leaving group L (N5) as described above can give compounds of structure XVI.

Compounds of formula I, represented by structure XVII can be prepared as shown in Scheme O.

Compounds of structure O1 can be converted to 2-iodo- or bromoindoles O₂. Typically, a strong base, such as n-butyllithium or s-butyllithium or lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed, with formation of the 2-indolyl anion generated in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically carried out in the range of −78° C. to ambient temperature. The 2-indolyl anion can then be quenched with an electrophilic source of halogen, including but not limited to iodine, bromine or N-bromosuccinimide to give compounds of structure O₂. Reaction of 2-iodo- or bromoindoles O₂ with a boronic acid (commonly referred to as a Suzuki reaction) or trialkyl stannane (commonly referred to as a Stille reaction) can give the compounds of structure XVII. The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis (triphenylphosphine) palladium (0), bis(triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand. The reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150° C. For the Suzuki reaction, a base is usually added. The base can be in aqueous solution, e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride. For the Stille reaction a copper co-catalyst, e.g., copper iodide, can be added.

Alternatively, indoles O1 can be converted to the indole-2-boronic acid or indole-2-trialkylstannane derivatives O3 by reacting the 2-indolyl anion described above with a trialkylborate or chlorotrialkyl stannane derivative, respectively. Compounds of type O3 can be reacted with aryl and heteroaryl bromides and iodides under similar conditions to those described above to form compounds of structure XVII.

Compounds of formula I, represented by structure XVIII can be prepared as shown in Scheme P.

Compounds of structure P1 can be converted to compounds P3 by treatment of P1 with an aryl or heteroaryl halide (P2) in the presence of organometallic catalysis. Such catalyst combinations can include palladium catalysts, e.g., palladium acetate and a source of copper, e.g., copper iodide. The reaction can be carried out in the presence of a base, e.g., cesium carbonate. The reaction can be carried out within a temperature range of ambient temperature to 150° C.

Compounds of the present invention, represented by structure XIX can be prepared as described in scheme Q below.

Compounds of structure XIX can be prepared by protecting an indole compound of structure Q1 as e.g., the N-Boc derivative Q2. Alternatively, other protecting groups which can be utilized but not limited to include, e.g., benzyl, alkyl or aryl sulfonyl, or trialkyl silyl. Treatment of Q2 with a strong base, e.g., lithium diisopropyl amide in an aprotic solvent, e.g., THF followed by quenching with a trialkylborate derivative can give the indolyl-2-boronic acid Q3. Reaction with an aryl or heteroaryl halide Q4 in the presence of palladium catalysis, e.g., tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand, can give the compound Q5. Removal of the protecting group can give Q6. Reaction with Q6 with a reactive functional group R₉ containing a suitable leaving group L as described above can give compounds of structure Q7. Cyanation of compound Q7 can give the compounds of structure XIX.

Compounds of formula I, represented by structure XX can be prepared as shown in Scheme R.

Compounds of structure R1 can be prepared by protecting an indole compound of structure R1 as e.g., the N-Boc derivative R2 as above. Compounds of structure R2 can be converted to 2-iodo- or bromoindoles R3. Typically, a strong base, such as n-butyllithium or s-butyllithium or lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed, with formation of the 2-indolyl anion generated in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically carried out in the range of −78° C. to ambient temperature. The 2-indolyl anion can then be quenched with an electrophilic source of halogen, including but not limited to iodine, bromine or N-bromosuccinimide to give compounds of structure R3. After removal of the protecting group, compounds of R4 can be reacted with aryl or heteroaryl boronic acids or esters (R5) (commonly referred to as a Suzuki reaction) to give compounds of structure R6. The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis (triphenylphosphine) palladium (0), bis(triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand. Reaction with R₆ with a reactive functional group R₉ containing a suitable leaving group L as described above can give compounds of structure XX.

Compounds of the present invention, represented by structure XXI can be prepared as described in scheme S below.

2-iodo- or bromoindoles of structure S1 can be reacted with alkenes in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XXI. The coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are similar to those described previously.

Compounds of formula I, represented by structure XXII can be prepared as shown in Scheme T.

2-Iodo- or 2-bromoindoles of structure T1 can be reacted with acetylenes in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XXII. The coupling reactions can be carried out by methods known to those skilled in the art. A typical set of reaction conditions includes reacting the indoles of structure T1 with an acetylene compound T2 in the presence of a source of palladium, a copper co-catalyst and an amine source. The reaction is carried out in a suitably unreactive solvent and conducted within a temperature range from ambient to 150° C.

Compounds of formula I, represented by structure XXIII can be prepared as shown in Scheme U.

Compounds of structure XXIII can be obtained from the reduction of compounds XXI and XXII. Conditions for the reduction can include, but are not limited to catalytic reduction, e.g., hydrogenation over a source of platinum or palladium in a suitable solvent, e.g., CH₂Cl₂, ether, THF, methanol or solvent combinations.

Compounds of the present invention, represented by structure XXIV can be prepared as described in scheme V below.

Indoles of structure V1 can be reacted with a suitable base, such as lithium diisopropylamide or potassium hexamethyldisilazide to generate the 2-indolyl anion in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically carried out in the range of −78° C. to ambient temperature. The 2-indolyl anion can then be quenched with a source of zinc halide, e.g., zinc halide metal or solutions containing them to give organozinc compounds of structure V2. Reaction of V2 with an arylhalide (V3) in the presence of a palladium catalyst (commonly referred to as the Negishi reaction) gives compounds of structure XXIV. Alternatively, 2-iodo or bromoindoles of structure V4, prepared from compounds V1 as described previously, can be reacted with organozinc compounds of structure V5 in the presence of a suitable palladium catalyst to give compounds of structure XXIV. The organozinc compound V5 can be derived from, e.g., an alkyl or alkenyl halide after treatment with activated zinc or an aryl or heteroaryl lithium or magnesium compound after treatment with zinc halide. Furthermore, the reactions of V2 or V4 can be carried out in the presence of a palladium source, e.g., as tetrakis (triphenylphosphine) palladium (0) or bis(triphenylphosphine) palladium (II) dichloride in a suitable solvent and at a temperature range from ambient to 150° C.

Compounds of formula I, represented by structure XXV-XXVIII can be prepared as shown in Scheme W.

2-Iodo- or bromoindoles of structure W1 can be reacted with acetylenes of structure W2 in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XXV. The coupling reactions can be carried out by methods known to those skilled in the art. A typical set of reaction conditions includes reacting the indoles of structure W1 with an acetylene compound W2 in the presence of a source of palladium, an optional copper co-catalyst and an amine source. The reaction is carried out in a suitably unreactive solvent and conducted within a temperature range from ambient to 150° C. Reaction with XXV with a reactive functional group R₉ containing a suitable leaving group L as described above can give compounds of structure XXVI.

2-iodo- or bromoindoles of structure W1 can also be reacted with alkenes in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XXVII. The coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are similar to those described previously. Reaction with XXVII with a reactive functional group R₉ containing a suitable leaving group L as described above can give compounds of structure XXVIII.

Compounds of formula I, represented by structure XXIX can be prepared as shown in Scheme X.

Indoles of structure X1 and be acylated with acyl halides of structure X2 to give compounds of structure XXIX. The reaction can be promoted with a Lewis acid. The choice of Lewis acid can be chosen from, but is not limited to aluminum chloride, ferric chloride, stannic chloride or diethyl aluminum. The reaction is typically carried out in a suitable non-reactive solvent including CH₂Cl₂, carbon disulfide or dichloroethane and is typically conducted within a temperature range of −20° C. to 80° C.

Compounds of formula I, represented by structure XXX can be prepared as shown in Scheme Y.

3-Cyanoindoles of structure Y1 can be converted to tetrazoles of structure Y2 by treatment with, e.g., sodium azide. Heating a mixture of Y2 and the reagent Y3 can give the 3-(1,2,4-oxadiazolyl)indole compound XXX. The reagent Y3 can be, e.g., an acyl halide or an acid derivative activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. The reaction can be carried out in a variety of solvents, including e.g., toluene, dioxane, pyridine and dichloroethane and can be carried out by heating Y2 and Y3 at a temperature range of 30° to 130° C.

Compounds of formula I, represented by structure XXXI can be prepared as shown in Scheme Z.

3-Cyanoindoles of structure Z1 can be treated with hydroxylamine to give hydroxyamidine compounds of formula Z2. Reaction of hydroxyamidines of structure Z2 with compounds of structure Z3 can give O-acylhydroxyamidines Z4. Compounds Z3 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. Heating compounds of structure Z4 in a non-reactive organic solvent, e.g., toluene, dichloroethane or dioxane in a temperature range of 30° C. to 150° C. can give compounds of structure XXXI.

Compounds of the present invention, represented by structure XXXII can be prepared as described in scheme AA below.

Ketoindoles of type AA1 can be converted to oximes of structure AA2 by heating the ketoindoles with hydroxylamine (free base or acid salt) in a suitable solvent. Bis-deprotonation of compounds of type AA2 with a strong organic base (e.g., n-butyllityium or sec-butyllithium or tert-butyllithium) followed by reaction with DMF can give compounds of formula XXXII.

Compounds of formula I, represented by structure XXXIII can be prepared as shown in Scheme AB.

3-Ketoindoles of structure AB1 can be homologated to vinylogous amides of structure AB3 by reaction with dialkyl amide dialkyl acetals AB2. The dialkyl amides can include e.g., lower alkyl amides such as formamide, acetamide and propionamide. Examples would include dimethlformamide dimethyl acetal and dimethyl acetamide dimethyl acetal. The reaction can be conducted by reacting AB1 and AB2 with or without additional solvent at a temperature from ambient to 150° C. Treatment of AB3 with hydroxylamine (free base or acid salt) in a suitable solvent can give compounds of structure XXXIII. The reaction is typically conducted within a temperature range from ambient to 120° C.

Compounds of formula I, represented by structure XXXIV can be prepared as shown in Scheme AC.

Vinylogous amides of structure AC1 (as prepared above) can be treated with hydrazines AC2 in a suitable organic solvent (DMF, alcohol or acetic acid) at temperatures ranging from ambient temperature to 150° C. to give compounds of structure XXXIV.

Compounds of the present invention, represented by structure XXXV can be prepared as described in scheme AD below.

Indole-3-carboxaldehydes of structure AD1 (as prepared in Scheme F) can be reacted with p-(toluenesulfonyl)methyl isocyanate (TOSMIC) in the presence of a base to give compounds of structure XXXV. Bases can include potassium carbonate or 1,8-diazabicyclo[5.4.0]undec-7-ene and the reaction can be carried out in a suitable organic solvent from ambient temperature to 150° C.

Compounds of formula I, represented by structure XXXVI and XXXVII can be prepared as shown in Scheme AE.

3-Indolecarboxylic acids of structure AE1 (from Scheme E) can be converted to amides of structure AE2. Compounds of structure AE2 can be activated by any of the standard methods. For example, the acid AE1 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of ammonia. Alternatively, the acid can be activated as the acid chloride or as the acyl imidazolide as described previously, followed by treatment of ammonia.

The indole-3-carboxamides of structure AE2 can be reacted with substituted aldehydes or ketones (AE3) containing a suitable leaving group L, in a suitable solvent at temperatures above ambient and up to 200° C. The reaction can be performed with or without added base to afford oxazoles of structure XXXVI.

The indole-3-carboxamides of structure AE2 can also be converted to thioamides of structure AE4 by treating the primary amides with Lawesson's reagent or phosphorous pentasulfide at or above ambient temperature in a suitable organic solvent. The resulting thioamides AE4 can be reacted with substituted aldehydes or ketones containing a suitable leaving group L (AE3), in a suitable solvent at temperatures above ambient and up to 150° C. The reaction can be performed with or without added base to afford thiazoles of structure XXXVII.

Compounds of the present invention, represented by structure XXXVIII and XXXIX can be prepared as described in scheme AF below.

3-Ketoindoles of structure AF1 can be halogenated (e.g., brominated) to give compounds of structure AF3. Suitable brominating agents can include but are not limited to phenyltrimethylammonium tribromide (AF2), N-bromosuccinimide or bromine and can be carried out in a variety of organic solvents.

Treatment of compounds AF3 with amides of type AF4 in a suitable solvent at temperatures above ambient and up to 200° C. with or without added base can give oxazoles of structure XXXVIII.

Treatment of compounds AF3 with thioamides of type AF5 in a suitable solvent at temperatures above ambient and up to 150° C. with or without added base can give thiazoles of structure XXXIX.

Compounds of formula I, represented by structure XL can be prepared as shown in Scheme AG.

Indoles of structure AG1 can be brominated or iodinated to give compounds of structure AG2. Brominating agents may include but are not limited to bromine or N-bromosuccinimide and iodinating reagents may include iodine monochloride or bis-trifluoroacetoxy iodobenzene. Reaction of 3-iodo- or bromoindoles AG2 with a boronic acid AG3 (commonly referred to as a Suzuki reaction) can give the compounds of structure XL. The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis (triphenylphosphine) palladium (0), bis(triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand. The reactions are carried out in a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150° C. and typically in the presence of a base e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride.

Alternatively, indole AG2 can be converted to the indole-3-boronic acid derivative AG5 by reacting the 3-haloindole AG2 with a strong organic base (alkyllithium or grignard reagent) and reacting the resultant anion with a trialkylborate reagent AG4. Compounds of type AG5 can be reacted with aryl and heteroaryl bromides and iodides under similar conditions to those described above to form compounds of structure XL.

Compounds of the present invention, represented by structure XLI can be prepared as described in scheme AH below.

3-iodo- or bromoindoles of structure AH1 can be reacted with alkenes AH2 in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XLI. The coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are similar to those described in Scheme AG.

Compounds of formula I, represented by structure XLII can be prepared as shown in Scheme AI.

3-Iodo- or bromoindoles of structure AI1 can be reacted with acetylenes AI2 in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XLII. The coupling reactions can be carried out by methods known to those skilled in the art. A typical set of reaction conditions includes reacting the indole of structure AI1 with an acetylene compound AI2 in the presence of a source of palladium, a copper co-catalyst and an amine source and carrying out the reaction at a temperature range of ambient to 150° C.

Compounds of the present invention, represented by structure XLIII and XLIV can be prepared as described in scheme AJ below.

Nitroanilines of structure AJ1 can be converted to indoles of structure XLIII by condensation and cyclization with nitriles of structure AJ2. The reaction can be carried out in a suitable organic solvent, e.g., DMF or dioxane. Treatment of compounds of structure XLIII with a base followed by reaction with a reactive functional group R₉ containing a suitable leaving group L can give the compounds of formula XLIV.

Compounds of formula I, represented by structure XLV-XLVIII can be prepared as shown in Scheme AK.

2-aminoindoles of structure XLV can be alkylated with a reactive functional group R₁₅ containing a suitable leaving group L in the presence of a base, e.g., sodium hydride or potassium carbonate in a suitable organic solvent to give compounds of structure XLVI. A second alkylation utilizing a reactive functional group R′₁₅ containing a suitable leaving group L similarly can give compounds of structure XLVII.

Acylation of compounds of structure XLV with acyl chlorides of structure AK1 can give compounds of structure XLVIII. The reaction is typically carried out in the presence of an organic base, e.g., a trialkylamine or an inorganic base, e.g., potassium carbonate in a suitable organic solvent.

Compounds of the present invention, represented by structure XLIX can be prepared as described in scheme AL below.

Indole-3-carboxylic acids of structure AL1 can be activated to give compounds of structure AL2. Compounds of structure AL2 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. Reaction of compounds of structure AL2 with hydroxyamidines of structure AL3 can give O-acylhydroxyamidines AL4. Hydroxyamidines may be obtained commercially or by treatment of nitrile compounds with hydroxylamine. Heating compounds of structure AL4 in a non-reactive organic solvent, e.g., toluene, dichloroethane or dioxane in a temperature range of 30° C. to 150° C. can give compounds of structure XLIX.

C. Methods of the Invention

The methods of the invention generally comprise administering a therapeutically effective amount of one or more compound of the present invention to a subject in need of treatment for HCV infection. In a preferred embodiment, a therapeutically effective amount of a composition comprising a compound of Formula I as described herein is administered to a subject in need of treatment. In another preferred embodiment, in another preferred embodiment, a compound or a composition used in the methods of the present invention includes a compound of Formula I as described herein wherein the compound of Formula I is not

Compound 1.

The compound(s) of the present invention may be administered to the subject via any drug delivery route known in the art. Specific exemplary administration routes include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, transdermal, and pulmonary. Individuals infected with HCV can be treated with the compounds of the present invention to prevent or reduce further replication of HCV.

The term therapeutically effective amount, as used herein, refers to an amount of a compound of the present invention effective to inhibit HCV translation, thereby effectively treating or ameliorating the HCV infection. The effect of the compound can be determined by analyzing (1) the presence of HCV-RNA; (2) the presence of anti-HCV antibodies; (3) the level of serum alanine amino transferase (ALT) and aspartate aminotransferase (AST) (ALT and AST are elevated in patients chronically infected with HCV); and (4) hepatocellular damage. The precise effective amount for a subject will depend upon the subject's body weight, size and health. Therapeutically effective amounts for a given patient can be determined by routine experimentation that is within the skill and judgment of the clinician.

For any compound, the therapeutically effective amount can be estimated initially either in cell culture assays or in relevant animal models, such as marmosets and tarmarins. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED₅₀ (the dose therapeutically effective in 50% of the population) and LD₅₀ (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, ED₅₀/LD₅₀. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage contained in such compositions is preferably within a range of circulating concentrations that include an ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

More specifically, the concentration-biological effect relationships observed with regard to the compound(s) of the present invention indicate an initial target plasma concentration ranging from approximately 0.1 μg/ml to approximately 100 μg/mL, preferably from approximately 1 μg/mL to approximately 50 μg/mL, more preferably from approximately 5 μg/mL to approximately 50 μg/mL, even more preferably from approximately 10 μg/mL to approximately 25 μg/mL. To achieve such plasma concentrations, the compounds of the invention may be administered at doses that vary from 0.1 μg to 100,000 mg, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and is generally available to practitioners in the art. In general the dose will be in the range of about 1 mg/day to about 10 g/day, or about 0.1 g to about 3 g/day, or about 0.3 g to about 3 g/day, or about 0.5 g to about 2 g/day, in single, divided, or continuous doses for a patient weighing between about 40 to about 100 kg (which dose may be adjusted for patients above or below this weight range, particularly children under 40 kg).

The exact dosage will be determined by the practitioner, in light of factors related to the subject that requires treatment. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

D. Metabolites of the Compounds of the Invention

Also falling within the scope of the present invention are the in vivo metabolic products of the compounds described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radio-labeled (e.g. C¹⁴ or H³) compound of the invention, administering it in a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating its conversion products from urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites may be done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no biological activity of their own.

E. Pharmaceutical Compositions of the Invention

While it is possible for the compounds of the present invention to be administered neat, it may be preferable to formulate the compounds as pharmaceutical compositions. As such, in yet another aspect of the invention, pharmaceutical compositions useful in the methods of the invention are provided. The pharmaceutical compositions of the invention may be formulated with pharmaceutically acceptable excipients such as carriers, solvents, stabilizers, adjuvants, diluents, etc., depending upon the particular mode of administration and dosage form. The pharmaceutical compositions should generally be formulated to achieve a physiologically compatible pH, and may range from a pH of about 3 to a pH of about 11, preferably about pH 3 to about pH 7, depending on the formulation and route of administration. In alternative embodiments, it may be preferred that the pH is adjusted to a range from about pH 5.0 to about pH 8.0.

More particularly, the pharmaceutical compositions of the invention comprise a therapeutically or prophylactically effective amount of one or more compound of the present invention, together with one or more pharmaceutically acceptable excipients. A therapeutically or prophylactically effective amount of a compound of the present invention includes a viral inhibitory amount of said compound or an amount effective for affecting viral IRES activity. By “viral inhibitory amount” it is meant an amount sufficient to inhibit viral replication or infectivity. By “an amount effective for affecting viral IRES activity” it is meant an amount sufficient to inhibit viral IRES mediated initiation and/or translation. Optionally, the pharmaceutical compositions of the invention may comprise a combination of compounds of the present invention, or may include a second active ingredient useful in the treatment of viral infections, such as anti-viral agents that include, but are not limited to: pegylated interferon, including by way of non-limiting example pegylated α-interferon; un-pegylated interferon, including by way of non-limiting example, un-pegylated α-interferon; ribavirin or prodrugs or derivatives thereof; a glucosidase inhibitor; protease inhibitors; polyermase inhibitors; p7 inhibitors; entry inhibitors, including fusion inhibitors such as Fuzeon™ (Trimeris); helicase inhibitors; a Toll-like receptor agonist, a caspase inhibitor, anti-fibrotics; drugs that target IMPDH (inosine monophosphate dehydrogenase inhibitors), such as Merimepadib™ (Vertex Pharmaceuticals Inc.); synthetic thymosin alpha 1 (ZADAXIN™, SciClone Pharmaceuticals Inc.); a glycosidase inhibitor; therapeutic viral vaccines, such as those produced by Chiron and Immunogenics; and immunomodulators, such as histamine.

Formulations of the present invention, e.g., for parenteral or oral administration, are most typically solids, liquid solutions, emulsions or suspensions, while inhaleable formulations for pulmonary administration are generally liquids or powders, with powder formulations being generally preferred. A preferred pharmaceutical composition of the invention may also be formulated as a lyophilized solid that is reconstituted with a physiologically compatible solvent prior to administration. Alternative pharmaceutical compositions of the invention may be formulated as syrups, creams, ointments, tablets, and the like.

The term “pharmaceutically acceptable excipient” refers to an excipient for administration of a pharmaceutical agent, such as the compounds of the present invention. The term refers to any pharmaceutical excipient that may be administered without undue toxicity. Pharmaceutically acceptable excipients are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there exists a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g., Remington's Pharmaceutical Sciences).

Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid; liquids such as oils, water, saline, glycerol and ethanol; wetting or emulsifying agents; pH buffering substances; and the like. Liposomes are also included within the definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions of the invention may be formulated in any form suitable for the intended method of administration. When intended for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.

Pharmaceutically acceptable excipients particularly suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.

In another embodiment, pharmaceutical compositions of the invention may be formulated as suspensions comprising a compound of the present invention in an admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension. In yet another embodiment, pharmaceutical compositions of the invention may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of suitable excipients.

Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

Additionally, the pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. This emulsion or suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propane-diol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

Generally, the compounds of the present invention useful in the methods of the present invention are substantially insoluble in water and are sparingly soluble in most pharmaceutically acceptable protic solvents and in vegetable oils. However, the compounds are generally soluble in medium-chain fatty acids (e.g., caprylic and capric acids) or triglycerides and have high solubility in propylene glycol esters of medium-chain fatty acids. Also contemplated in the invention are compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.), for example by esterification, glycosylation, PEGylation, etc.

In a preferred embodiment, the compounds of the present invention may be formulated for oral administration in a lipid-based formulation suitable for low solubility compounds. Lipid-based formulations can generally enhance the oral bioavailability of such compounds. As such, a preferred pharmaceutical composition of the invention comprises a therapeutically or prophylactically effective amount of a compound of the present invention, together with at least one pharmaceutically acceptable excipient selected from the group consisting of: medium chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants such as polyoxyl 40 hydrogenated castor oil.

In an alternative preferred embodiment, cyclodextrins may be added as aqueous solubility enhancers. Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin. A particularly preferred cyclodextrin solubility enhancer is hydroxypropyl-β-cyclodextrin (HPBC), which may be added to any of the above-described compositions to further improve the aqueous solubility characteristics of the compounds of the present invention. In one embodiment, the composition comprises 0.1% to 20% hydroxypropyl-β-cyclodextrin, more preferably 1% to 15% hydroxypropyl-β-cyclodextrin, and even more preferably from 2.5% to 10% hydroxypropyl-β-cyclodextrin. The amount of solubility enhancer employed will depend on the amount of the compound of the present invention in the composition.

F. Combination Therapy

It is also possible to combine any compound of the present invention with one or more other active ingredients useful in the treatment of HCV infection, including compounds, in a unitary dosage form, or in separate dosage forms intended for simultaneous or sequential administration to a patient in need of treatment. When administered sequentially, the combination may be administered in two or more administrations. In an alternative embodiment, it is possible to administer one or more compounds of the present invention and one or more additional active ingredients by different routes.

The skilled artisan will recognize that a variety of active ingredients may be administered in combination with the compounds of the present invention that may act to augment or synergistically enhance the viral inhibiting activity of the compounds of the invention. Such active ingredients include anti-HCV agents. Anti-HCV agents include agents that target the virus as well as agents that have an immunomodulatory effect. For example, anti-HCV agents include, but are not limited to, interferon, including, for example without limitation, IFN-α, ribavirin or prodrugs or derivatives thereof; a glucosidase inhibitor, protease inhibitors, polymerase inhibitors, helicase inhibitors, a Toll-like receptor agonist, a caspase inhibitor and a glycosidase inhibitor. Furthermore, the compounds of the invention may also be administered in combination with other compounds that affect IRES activity known to one of skill in the art.

According to the methods of the invention, the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art. When delivered in alternation therapy, the methods of the invention may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together. Various sequences of intermittent combination therapy may also be used.

To assist in understanding the present invention, the following Examples are included. The experiments relating to this invention should not, of course, be construed as specifically limiting the invention and such variations of the invention, now known or later developed, which would be within the purview of one skilled in the art are considered to fall within the scope of the invention as described herein and hereinafter claimed.

EXAMPLES

The present invention is described in more detail with reference to the following non-limiting examples, which are offered to more fully illustrate the invention, but are not to be construed as limiting the scope thereof. The examples illustrate the preparation of certain compounds of the invention, and the testing of these compounds in vitro and/or in vivo. Those of skill in the art will understand that the techniques described in these examples represent techniques described by the inventors to function well in the practice of the invention, and as such constitute preferred modes for the practice thereof. However, it should be appreciated that those of skill in the art should in light of the present disclosure, appreciate that many changes can be made in the specific methods that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1 Preparation of Compounds of the Invention Example 1A Preparation of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (compound 5)

Step A: A solution of 6-methoxyindole (10.0 g, 68.0 mmol) in DMF (120 mL) was cooled to 0° C. and treated with chlorosulfonyl isocyanate (7.72 mL, 88.4 mmol). After the addition, the reaction mixture was stirred at this temperature for 1 h. The dark solution was poured into ice water (600 mL) and the light brown solid was collected by filtration, washed with additional H₂O and dried to afford 9.9 g (85%) of 6-methoxy-1H-indole-3-carbonitrile as a light brown solid.

Step B: To a solution of 6-methoxy-1H-indole-3-carbonitrile (9.9 g, 57.6 mmol) in DMF (150 mL) was added NaH (60% dispersion in mineral oil, 3.45 g, 86.3 mmol). The reaction mixture was stirred for 15 min and then ethyl iodide (5.53 mL, 69.1 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with H₂O and extracted with EtOAc (2×). The organic phases were washed with H₂O (3×) and saturated NaCl and then dried and concentrated to a semi-solid. The crude product was purified via column chromatography on silica gel (200 g) using CH₂Cl₂/hexanes (50-100%) as eluent to yield 6-methoxy-1-ethyl-1H-indole-3-carbonitrile as a tan solid.

Utilizing steps A and B above and substituting different indoles and alkyl halides gave the following compounds: Compounds 43, 45, 51, 52, 108, 109, 115, 118, 120, 123, 126, 179 and 714.

Example 1B Preparation of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (compound 9)

Step A: To a solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (2.85 g, 14.2 mmol), prepared by example 1A, step B, in CH₂Cl₂ (40 mL) was added a 1M solution of BBr₃ in CH₂Cl₂ (28.5 mL, 28.5 mmol) at 0° C. The mixture was allowed to warm to room temperature and kept for 2.5 h. The dark reaction mixture was then poured onto ice and sufficient 1M NaOH was added until the pH was 8-9. The product was extracted with CH₂Cl₂ (3×) and the combined organic phases were washed with saturated NaHCO₃, H₂O and saturated NaCl. After drying over MgSO₄, the solution was concentrated and the product was purified by chromatography (EtOAc/CH₂Cl₂, 0-10%) to afford 2.15 g (82%) of 6-hydroxy-1-ethyl-1H-indole-3-carbonitrile as a yellow solid.

Step B: To a solution 6-hydroxy-1-ethyl-1H-indole-3-carbonitrile (80 mg, 0.43 mmol) in 5 mL of methyl ethyl ketone was added anhydrous K₂CO₃ (71 mg, 0.52 mmol) and iodomethane (0.05 mL, 0.60 mmol). After stirring overnight at reflux, the reaction mixture was cooled, diluted with H₂O and extracted with EtOAc (3×). The combined organic phases were dried and concentrated. Flash chromatography (CH₂Cl₂) gave 94 mg (100%) of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile as a white wax.

In similar fashion, following steps A and B, above, the following compounds were also prepared: compounds 6, 10, 11, 12 and 24

Example 1C Preparation of 5-(4-methoxyphenyl)-5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile (compound 44)

A mixture of p-iodoanisole (85 mg, 0.36 mmol), anhydrous K₃PO₄ (102 mg, 0.48 mmol), CuI (4.6 mg, 0.024 mmol) and N,N′-Dimethyl cyclohexane-1,2-diamine (14 mg, 0.096 mmol) was added to 5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile (45 mg, 0.24 mmol), prepared as described by the method of example 1A, step A, in anhydrous toluene (0.4 mL). After heating at reflux for 24 h, the solvent was evaporated under vacuum. The residue was dissolved with CH₂Cl₂ (5 mL) and the mixture was filtered. The filtrate was concentrated to afford crude product, which was purified by silica gel chromatography using EtOAc/petroleum ether (1:4) as eluent to yield 5-(4-methoxyphenyl)-5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile.

Utilizing the procedure above and substituting different aryl iodides gave the following compounds: compounds 4, 8, 102, 103, 111, 112, 117, 119, 124, 125, 127, 154.

Example 1D Preparation of 1-ethyl-6-(pyrazin-2-yloxy)-1H-indole-3-carbonitrile (compound 13)

To a solution of 1-ethyl-6-hydroxy-1H-indole-3-carbonitrile (60 mg, 0.32 mmol) prepared as described in example 1A, step A, in DMF (5 mL) was added K₂CO₃ (55 mg, 0.40 mmol) and 2-chloropyridazine (45 mg, 0.40 mmol). The mixture was heated at 110° C. for 18 h. After cooling to room temperature, the reaction mixture was diluted with H₂O and extracted with EtOAc (3×). The combined organic phases were washed with H₂O and saturated NaCl, dried and concentrated. The product was isolated by chromatography (EtOAc/CH₂Cl₂, 1-3%) over silica gel to afford 76 mg (96%) of the title compound, 1-ethyl-6-(pyrazin-2-yloxy)-1H-indole-3-carbonitrile, as an off-white solid.

Example 1E Preparation of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid phenylamide (compound 15)

Step A: A solution of methyl 3-cyano-1-ethyl-1H-indole-6-carboxylate (1.60 g, 7.02 mmol), prepared by the method described in example 1A from methyl 1H-indole-6-carboxylate, in THF (35 mL) was treated with 1N NaOH (7.7 mL, 7.7 mmol) and heated at reflux for 2.5 h. After cooling to room temperature, most of the THF was removed and the solution was diluted with H₂O and extracted with ether (2×). The ether extracts were discarded. The aqueous phase was then acidified with 6N HCl to pH 2 and then extracted with EtOAc (3×). The EtOAc layers were combined, washed with saturated NaCl and then dried and concentrated to afford 1.43 g (95%) of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid as a white solid.

Step B: A suspension of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid (0.42 g, 1.96 mmol) in CH₂Cl₂ (15 mL) was cooled to 0° C. The suspension was treated with DMF (2 drops) and then oxalyl chloride (0.34 mL, 3.92 mmol) was added via syringe during 2 minutes after which the ice bath was removed and the reaction mixture was allowed to warm to ambient temperature during 1.5 h during which time the reaction became a yellow solution. The solution was then concentrated in vacuo to afford 0.46 g (quantitative yield) of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride as a yellow solid.

Step C: A suspension of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride (70 mg, 0.30 mmol) in THF (5 mL) was cooled to 0° C. and treated with aniline (0.08 mL, 0.90 mmol). After the addition the reaction was warmed to ambient temperature and after stirring for an additional 16 hours, the reaction mixture was diluted with H₂O and extracted with EtOAc (2×). The combined organic phases were washed with saturated NaCl and then dried and concentrated to afford the product. Chromatography (EtOAc/CH₂Cl₂, 2/98) over silica gel gave 44 mg (51%) of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid phenylamide.

Utilizing essentially the procedure above gave the following compound: Compound 89.

Example 1F Preparation of t-butyl (3-cyano-1-ethyl-1H-indol-6-yl)-carbamate (compound 16)

A solution of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid (0.60 g, 2.80 mmol) from Example 1E, step A, in t-butanol (20 mL) was treated with Et₃N (0.46 mL, 3.36 mmol) and diphenylphosphoryl azide (0.73 mL, 3.36 mmol) and then heated at reflux for 4 h. After cooling to room temperature, most of the t-butanol was removed in vacuo to give an oil, which was then dissolved in EtOAc. After washing with H₂O, the organic phase was back-extracted with EtOAc and the organic layers were combined and washed sequentially with additional H₂O, saturated NaHCO₃ and saturated NaCl. The organic phase was dried, concentrated and the resulting crude product was purified by chromatography over silica gel using EtOAc/CH₂Cl₂ (0-1%) to afford 0.52 g (65%) of t-butyl (3-cyano-1-ethyl-1H-indol-6-yl)-carbamate as a white solid.

The following compound was made in similar fashion: compound 90.

Example 1Ga Preparation of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile via Suzuki route (compound 55)

Step A: A 2M solution of lithium diisopropyl amide in THF/hexanes (Acros) (3.9 mL, 7.8 mmol) was diluted with THF (5 mL) in a flame-dried flask. After cooling the reaction to −30° C., a solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.30 g, 6.5 mmol) in THF (10 mL) was added dropwise during 10 min, maintaining the temperature at −30° C. After stirring for an additional 30 min at this temperature, a solution of iodine (2.31 g, 9.1 mmol) in THF (5 mL) was added during 10 min. After the addition, the reaction was warmed to ambient temperature during 1 h. The reaction was then diluted with ice-H₂O and extracted with EtOAc (2×). The combined organic phases were washed with 1M sodium thiosulfate and saturated NaCl and then concentrated to a brown solid. Chromatography (CH₂Cl₂/hexanes, 1/1) over silica gel gave 1.31 g (62%) of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile as an off-white solid.

Step B: A mixture of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (1.25 g, 3.83 mmol), 4-(4,4,5,5-tetramethyl)-1,3-2-dioxaboralanyl-2-yl-aniline (0.96 g, 4.90 mmol), CsF (1.46 g, 9.58 mmol) and Pd(PPh₃)₂Cl₂ (110 mg, 0.15 mmol) in DME (20 mL) was added to a flask and alternatively evacuated and flushed with N₂. The reaction was then heated at reflux for 24 h and then cooled to room temperature. The reaction mixture was diluted with H₂O and extracted with EtOAc (2×). The combined organic phases were washed with H₂O and saturated NaCl and then dried over MgSO₄ and concentrated. The crude reaction mix purified by flash chromatographt on silica gel using EtOAc/CH₂Cl₂ (5/95) as eluent to afford 765 mg (69%) of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile as a yellow solid.

Utilizing essentially the same procedure described above and substituting different boronic acids gave the following compounds: compounds 19, 20, 21, 22, 53, 63, 70, 71, 74, 76, 77, 79, 80, 100, 110, 229, 239, 240, 247, 250, 254, 255, 256, 257, 258, 259, 260, 281, 282, 283, 284, 286, 335, 336, 337, 338, 339, 347, 348, 426, 427, 428, 429, 476, 543, 578, 758.

Example 1Gb Preparation of 2-(4-aminophenyl)-1-butyl-6-methoxy-1H-indole-3-carbonitrile via alternative Suzuki route

To a solution of (i-Pr)₂NH (1.35 mL, 9.65 mmol) in THF (30 mL) cooled to −78° C. was added n-BuLi (3.7 mL, 2.5M in hexanes, 9.21 mmol) in one portion. The acetone/dry ice bath was exchanged for ice/water bath and the solution was stirred further for 40 min. The solution was cooled to −78° C. and solution of 1-butyl-6-methoxy-1H-indole-3-carbonitrile, prepared as in example 1A (2.0 g, 8.77 mmol) in THF (10 mL) was added dropwise. This solution was stirred for 15 min at −78° C., following by 20 min at −20° C. Trimethyl borate (1.0 mL, 8.77 mmol) was added, the reaction mixture was stirred for 15 min at −20° C. after which the cooling bath was removed and this solution was stirred further at room temperature for 1 h. A solution of K₃PO₄ was added (11.7 mL, 3M aqueous solution, 35.1 mmol) followed by a solution of 4-iodoaniline (2.5 g, 11.40 mmol) and PdCl₂dppf catalyst (640 mg, 0.88 mmol) in DMF (40 mL, plus a 5 mL rinse). The reaction mixture was stirred overnight (ca. 18 h.) and then water (80 mL) was added and the product was extracted with EtOAc (3×50 mL). The combined organic fractions were dried over MgSO₄, filtered and concentrated under reduced pressure. The crude product was purified via flush chromatography on silica gel (5→60% EtOAc/Hexanes as eluant) to afford the desired 2-(4-aminophenyl)-1-butyl-6-methoxy-1H-indole-3-carbonitrile as a tan solid (2.4 g, 86% yield).

The following compounds were prepared in similar fashion utilizing other indole and aryl and hereroaryl bromides and iodides: Compounds 656, 659, 660, 661, 682, 683, 712, 731, 732, 733, 806, 807, 808, 809, 810, 811, 812, 813, 814, 827.

Example 1Gc Preparation of 2-(4-aminophenyl)-6-methoxy-1-propyl-1H-indole-3-carbonitrile via Negishi route

A nitrogen-purged flask fitted with a septum and a nitrogen needle was charged with dry THF (all additions performed by syringe) (20 mL). Diisopropylamine (Aldrich Sure-Seal, 2.00 mL, 14.3 mmol) was added, and the solution was cooled to 0° C. n-Butyllithium (8.50 mL of 1.6 M solution in hexane, 13.6 mmol) was added slowly. The flask was allowed to warm to room temperature briefly, and then was cooled to −78° C. A concentrated THF solution of 6-methoxy-1-propyl-1H-indole-3-carbonitrile (2.77 g, 12.9 mmol; prepared analogously to compound 5 of Example 1A) was added slowly, and the resulting solution was maintained at −78° C. for 30 min. The flask was then transferred to a water-ice bath and allowed to come to 0° C. for about 15 minutes. The solution was once again cooled to −78° C., and ZnCl₂ (0.5 M solution in THF, 27.0 mL, 13.5 mmol) was slowly added. A precipitate was observed at this point, which may have been the bis(indole)zinc compound, but the solution became homogeneous when the entire volume of zinc chloride solution was added. After about 10 minutes, the solution was allowed to come to room temperature, and a THF solution (5 mL) of 4-iodoaniline (3.47 g, 15.8 mmol) and triphenylphosphine (338 mg, 1.29 mmol) was added. The septum was removed, and solid Pd₂(dba)₃ (295 mg, 0.322 mmol) was added. A reflux condenser was fitted to the flask, and the solution was degassed by three successive cycles of vacuum pumping/N₂ purging. The solution was then heated to reflux overnight. After cooling to room temperature, the solution was poured into 4 volumes of water, and 4 volumes of ethyl acetate were added. The resulting mixture was vigorously stirred for 30 minutes, then filtered through celite (with ethyl acetate washing) to remove solid Zn- and Pd-containing material. The phases were separated, and the aqueous phase was extracted with more ethyl acetate. The organic phases were washed in sequence with saturated brine, combined, dried over anhydrous sodium sulfate, filtered and evaporated. A solid precipitate formed at this point, which was sufficiently pure product and was collected by trituration with ether and filtration. The remaining material was purified by column chromatography (eluting 1:2 ethyl acetate-hexane on silica gel 60). Total yield of the product, 2-(4-amino-phenyl)-6-methoxy-1-propyl-1H-indole-3-carbonitrile, was 2.75 g (8.99 mmol, 70%).

The following compounds were made using essentially the same procedure and substituting other aryl or heteroaryl iodides or bromides: Compounds 393, 408, 430, 431, 436, 437, 438, 459, 460, 461, 462, 483, 484, 632, 633, 634, 635, 636, 650, 651.

Example 1Gd Preparation of 1-ethyl-2-(3-hydroxyphenyl)-6-methoxy-1H-indole-3-carbonitrile (Compound 288)

Step A: A solution of THF (60 mL) and diisopropylamine (5.5 mL, 39 mmol) was cooled to −78° C. n-Butyllithium (14.5 mL, 2.5M in hexanes, 36.2 mmol) was added dropwise over 5 minutes. The LDA mixture was stirred at −78° C. for 10 minutes, and then at 0° C. for 20 minutes. The solution was re-cooled to −78° C. 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (5.0 g, 25 mmol), prepared as in example 1A, was taken up in THF (30 mL) and added dropwise to the LDA mixture over 15 minutes. The reaction was stirred at −78° C. for 10 minutes, and at 0° C. for 30 minutes. Once again, the reaction mixture was cooled to −78° C. Tributyltin iodide (10 mL, 35 mmol) was added dropwise. This was stirred at −78° C. for 15 minutes, and then at 0° C. for 30 minutes. The reaction mixture was absorbed onto silica gel and concentrated. Purification by chromatography (CH₂Cl₂) yielded 1-ethyl-6-methoxy-2-tributylstannanyl-1H-indole-3-carbonitrile (12.05 g, 98%).

Step B: 1-Ethyl-6-methoxy-2-tributylstannanyl-1H-indole-3-carbonitrile (1.0 g, 2.05 mmol), prepared in step A, was combined with 3-iodophenol (474 mg, 2.15 mmol), Pd(PPh₃)₂Cl₂ (67 mg, 0.102 mmol), CuI (75 mg, 0.39 mmol) and THF (4.0 mL). This mixture was heated at 65° C. overnight. The reaction mixture was diluted in EtOAc, and was filtered through celite. The filtrate was concentrated and the residue was purified by silica gel chromatography (4:1, CH₂Cl₂/EtOAc) to yield crude product. Ether trituration yielded 1-ethyl-2-(3-hydroxy-phenyl)-6-methoxy-1H-indole-3-carbonitrile (430 mg, 72%) as a yellow-white solid.

The following compounds were prepared similarly as above, using other commercially available iodides and bromides, or using iodides derived from a one step amidation of p-iodophenylsulfonyl chloride: Compounds 275, 276, 277, 278, 331, 363, 364, 373, 374, 375, 474, 475, 678.

Example 1Ge Preparation of ethanesulfonic acid [4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide via Heck route (compound 519)

Step A: A solution of 6-difluoromethoxy-1-ethyl-1H-indole (402.8 mg, 2.04 mmol), ethanesulfonic acid (4-iodo-phenyl)-amide (712.1 mg, 2.29 mmol), cesium carbonate (733.2 mg, 3.82 mmol), triphenylphosphine (33.1 mg, 0.13 mmol) and palladium acetate (5.7 mg, 0.025 mmol) in DMA (5 ml) was heated to 135° C. for 48 h. The reaction mixture was diluted with water and extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine, dried over MgSO₄, and then concentrated. The residue was purified via column chromatogrphy on silica gel (25 g) using EtOAc/Hexanes (10-20%) as eluent to afford 298.2 mg (37.1% yield) of ethanesulfonic acid [4-(6-difluoromethoxy-1-ethyl-1H-iodo-2-yl)-phenyl]-amide, compound 516, as a light brown solid.

Step B: Following the procedure 1A, step A, ethanesulfonic acid [4-(6-difluoromethoxy-1-ethyl-1H-iodo-2-yl)-phenyl]-amide was converted to ethanesulfonic acid [4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide, compound 519.

Following steps A and B above, the following compounds were prepared in similar fashion: Compounds 343, 344, 345, 346, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 515, 517, 518, 520, 521, 522, 523, 524, 575, 577, 579, 580, 611, 612, 613, 614

Example 1H Preparation of 1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-1H-indole-3-carbonitrile (compound 67)

A mixture of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (150 mg, 0.46 mmol), prepared as described in example 1Ga, step A, 4-fluorophenylacetylene (80 mg, 0.0.69 mmol), bis(triphenylphosphine) palladium (II) dichloride (6 mg, 0.009 mmol) and CuI (4 mg, 0.018 mmol) was added to a sealable tube and alternatively evacuated and flushed with N₂. To the tube was then added DMF (4 mL) and Et₃N (0.25 mL, 1.84 mmol) and the reaction was heated at 80° C. for 20 h and then cooled to room temperature. The reaction mixture was diluted with H₂O and extracted with EtOAc (2×). The combined organic phases were washed with H₂O (3×) and saturated NaCl and then dried over MgSO4 and concentrated. The crude reaction mix was absorbed on silica gel (0.6 g) and chromatographed over silica gel using EtOAc/hexanes (10-20%) as eluent to afford 120 mg (82%) of 1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-1H-indole-3-carbonitrile as a yellow solid.

Utilizing essentially the same procedure described above and substituting different acetylene derivatives gave the following compounds: compounds 64, 65, 66, 68, 69, 91, 92, 93, 94, 95, 96, 133, 134, 135, 136, 137, 143, 144, 145, 146, 147, 148, 149, 150, 151, 158, 159, 160, 161, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 184, 185, 186, 187, 188, 196, 197, 198, 199, 200, 201, 202, 223, 230, 231, 232, 233, 234, 235, 236, 237, 238.

Example 1I Preparation of 1-ethyl-3-(5-ethyl-[1,2,4]oxadiazol-3-yl)-6-methoxy-1H-indole (compound 28)

Step A: A solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.00 g, 5.00 mmol) in MeOH (10 mL) was treated with a 50% aqueous solution of hydroxylamine (0.38 mL, 6.25 mmol) and heated at reflux for 18 h. After cooling to room temperature, the heterogeneous mixture was filtered to afford 525 mg of desired product as a tan solid. The filtrate was concentrated to an oil, which was then dissolved in CH₂Cl₂ and chromatographed over silica gel using EtOAc/CH₂Cl₂ (15-50%) to afford an additional 295 mg of product as a tan solid. Total yield of 1-ethyl-N-hydroxy-6-methoxy-1H-indole-3-carboxamidine was 820 mg (70%).

Step B: The N-hydroxycarboxamidine above (50 mg, 0.21 mmol), polystyrene-diisopropylethylamine 165 mg, 3.90 mmol/g loading) and propionyl chloride (0.03 mL, 0.32 mmol) in CH₂Cl₂ (10 mL) were placed in a tube and rotated for 22 h at room temperature. After this time, trisamine resin (77 mg, 2.71 mmol/g loading) was then added and the tube rotated for an additional 30 min at room temperature. Solids were filtered and then the filtrate was concentrated and diluted with toluene (5 mL) and heated at 110° C. overnight. The crude reaction mixture was concentrated and purified by chromatography (EtOAc/CH₂Cl₂, 2/98) to afford 27 mg (46%) of 1-ethyl-3-(5-ethyl-[1,2,4]oxadiazol-3-yl)-6-methoxy-1H-indole as a white solid.

The following compound was prepared utilizing the above procedure with substitution of the appropriate acyl halide: compound 29.

Example 1J Preparation of 1-ethyl-6-methoxy-3-(5-ethyl-[1,3,4]oxadiazol-2-yl)-1H-indole (compound 54)

Step A: A mixture of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.00 g, 5.00 mmol) in toluene (30 mL) was treated with triethylamine hydrochloride (1.03 g, 7.50 mmol) and sodium azide (0.49 g, 7.50 mmol) and was heated at reflux for 16 h. After cooling to room temperature, the reaction mixture was diluted with saturated NaHCO₃ and extracted with EtOAc. The organic layer was then washed with additional NaHCO₃ (2×). The combined aqueous phases were acidified to pH 2 with 6N HCl. The resultant thick precipitate was extracted with hot EtOAc (3×) and the combined organic phases were washed with saturated NaCl and dried and concentrated to give 0.55 g (45%) of 1-ethyl-6-methoxy-3-(1H-tetrazol-5-yl)-1H-indole as a yellow solid.

Step B: A suspension of the tetrazole above (50 mg, 0.21 mmol) and propionyl chloride (0.03 mL, 0.31 mmol) in dichloroethane (5 mL) was heated at reflux for 21 h. After cooling the reaction mixture to room temperature, polystyrene trisamine resin (70 mg, 3.4 meq/g) was added and the reaction was rotated for 4 h at room temperature. After filtering off the resin, and removal of the solvent, the crude product was absorbed on silica gel and the product was isolated by silica gel chromatography (EtOAc/CH₂Cl₂, 5-10%) to afford 30 mg (53%) of 1-ethyl-6-methoxy-3-(5-ethyl-[1,3,4]oxadiazol-2-yl)-1H-indole as a tan solid.

Example 1K Preparation of ethyl 5-difluoromethoxy-1-(4-methoxyphenyl)-2-methyl-1H-indole-3-carboxylate (compound 49)

Freon-22 (HCF₂C1) gas was bubbled into a solution of ethyl 5-hydroxy-1-(4-methoxyphenyl)-2-methyl-1H-indole-3-carboxylate (250 mg, 0.77 mmol) in CH₂Cl₂ (5 mL) at 0° C. containing a small amount of tetrabutylammonium bromide as a phase transfer catalyst. A 50% solution of NaOH was added dropwise at 0° C. After the addition, the mixture was stirred at 0° C. for 2 h. After the addition of H₂O, the organic phase was separated and washed with brine and dried over Na₂SO₄. The solvent was then concentrated and the residue was purified by column chromatography over silica gel using EtOAc/petroleum ether (1/2) as eluent to yield the desired product in 40% yield.

The following compounds were prepared utilizing the above procedure with substitution of the appropriate hydroxyindole: compounds 18, 46, and 50.

Example 1L Preparation of 1-[5-methoxy-1-(4-methoxyphenyl)-1-H-indol-3-yl]-ethanone (compound 42)

5-Methoxy-1-(4-methoxyphenyl)-1-H-indole (50 mg, 0.2 mmol), prepared by the method of example 1C, was dissolved in 1 mL of CH₂Cl₂ at 0° C. Et₂AlCl (300 μL, 1M in hexanes, 0.3 mmol) was then added. After stirring at 0° C. for 30 min, a solution of acetyl chloride (22 μL, 0.3 mmol) in 1 mL of CH₂Cl₂ was added dropwise. This was stirred at 0° C. for a further 90 min. The reaction mixture was quenched with H₂O and was extracted with CH₂Cl₂ and concentrated in vacuo. Purification by column chromatography on silica gel EtOAc/CH₂Cl₂ (5/95) yielded the title compound as a white solid (42 mg, 71%).

Utilizing essentially the same procedure described above and substituting different acyl chlorides, the following compounds were prepared: compounds 32, 33, 34, 37, 38, 39, 47, 48.

Example 1M Preparation of 1-ethyl-3-isoxazol-3-yl-6-methoxy-1-H-indole (compound 57)

Step A: A mixture of 1-(1-ethyl-6-methoxy-1-H-indole-3-yl)ethanone (200 mg, 0.92 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, hydroxylamine hydrochloride (128 mg, 1.84 mmol), NaOAc (151 mg, 1.84 mmol) and EtOH (7 mL) was heated at 85° C. for 4 h. The reaction mixture was then partitioned between H₂O and EtOAc. The organic phase was dried and concentrated in vacuo. Purification by column chromatography using EtOAc/CH₂Cl₂ (1/9) yielded 1-(1-ethyl-6-methoxy-1-H-indole-3-yl)ethanone oxime as a white solid (189 mg, 92%).

Step B: 1-(1-Ethyl-6-methoxy-1-H-indole-3-yl)ethanone oxime (100 mg, 0.43 mmol) was dissolved in THF (900 μL) at 0° C. n-BuLi (450 μL, 2.5 M in hexanes, 1.12 mol) was added dropwise, resulting in instant precipitation of solids. DMF (70 μL, 0.9 mol) in 260 μL of was then added dropwise. This was stirred at 0° C. for 1 h, then at room temperature for 1 h. The reaction mixture was pipetted into a mixture containing 1 mL of H₂O, 1 mL of THF, and 100 μL of concentrated H₂SO₄. This mixture was heated at 75° C. for 1 h and then was partitioned between H₂O and EtOAc. The organic phase was dried and concentrated. Purification by column chromatography (CH₂Cl₂) yielded 1-ethyl-3-isoxazol-3-yl-6-methoxy-1-H-indole product as a white solid (13 mg, 12%).

Example 1N Preparation of 1-ethyl-3-isoxazol-5-yl-6-methoxy-1H-indole (compound 58)

1-(1-Ethyl-6-methoxy-1H-indol-3-yl)ethanone (100 mg, 0.46 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, was heated with 1.5 mL of dimethylformamide dimethylacetal and 100 μL of pyrrolidine at 110° C. overnight. The dimethylformamide dimethylacetal was then concentrated in vacuo. The residue was redissolved in 1.25 mL of EtOH and 250 μL of H₂O, and was treated with hydroxylamine hydrochloride (66 mg, 0.95 mmol) and heated at 80° C. for 2 h. Partitioning between H₂O and EtOAc and drying and concentration of the organic phase followed by purification by silica gel chromatography (EtOAc/CH₂Cl₂, 5/95) gave 1-ethyl-3-isoxazol-5-yl-6-methoxy-1H-indole as a white solid (72 mg, 66%).

Utilizing essentially the same procedure described above, the following compound was prepared: Compound 60.

Example 1O Preparation of 1-ethyl-6-methoxy-3-(2H-pyrazol-3-yl)-1H-indole (compound 59)

1-(1-Ethyl-6-methoxy-1H-indol-3-yl)-ethanone (100 mg, 0.46 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, was heated with 1.5 mL of dimethylformamide dimethyl acetal and 100 μL pyrrolidine at 110° C. overnight. The DMF dimethyl acetal was removed in vacuo. The residue was redissolved in 3 mL of acetic acid, hydrazine hydrate (70 μL, 1.38 mmol) was added, and the mixture was heated to 100° C. for 2 h. The acetic acid was removed in vacuo, and the residue was partitioned between EtOAc and saturated NaHCO₃. The organic phase was dried and concentrated and the product purified by silica gel chromatography (EtOAc/Hex, 1/1) to give 59 mg of 1-ethyl-6-methoxy-3-(2H-pyrazol-3-yl)-1H-indole (54%) as a colorless semisolid. Trituration in Et₂O gave a white crystalline powder.

The following compound was prepared utilizing the above procedure: Compound 61.

Example 1P Preparation of methyl 1-ethyl-3-oxazol-5-yl-1H-indole-6-carboxylate (compound 72)

Step A: 1-Ethyl-1H-indole-6-carboxylic acid methyl ester (900 mg, 4.45 mmol) was dissolved in DMF (3.3 mL). This was added dropwise to an ice-cold solution of POCl₃ (430 μL, 4.5 mmol) in DMF (1.5 mL). The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was then treated with 6N NaOH (3.5 ml). The mixture was then partitioned between H₂O and ethyl acetate. Purification by silica gel chromatography (5-10% EtOAc/CH₂Cl₂) yielded 1-ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (985 mg, 96%) as a white solid.

Step B: 1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (100 mg, 0.42 mmol), TOSMIC (100 mg, 0.52 mmol), K₂CO₃ (178 mg, 1.29 mmol), and MeOH (800 μL) were heated at 80° C. overnight. The reaction mixture was then partitioned between H₂O and ether. After drying and concentrating the organic phase, the product was purified by silica gel chromatography (EtOAc/CH₂Cl₂, 10/90) to give methyl 1-ethyl-3-oxazol-5-yl-1H-indole-6-carboxylate (26 mg, 23%) as an off-white solid.

Example 1Q Preparation of methyl 1-ethyl-3-oxazol-2-yl-1H-indole-6-carboxylate (compound 75)

Step A: 1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (800 mg, 3.5 mmol), prepared as shown in example 1P, step A, was dissolved in acetone (98 mL). A solution of KMnO₄ (655 mg, 4.15 mmol) in H₂O (31 mL) was added. The reaction mixture was stirred at room temperature for 90 minutes. Another addition of KMnO₄ (108 mg) in H₂O (6 mL), followed by stirring for another 45 minutes was required to drive the reaction to completion. The reaction mixture was then quenched with 10% H₂O₂ (1.5 mL). The mixture was filtered through celite. The filtrate was stripped down under vacuum to roughly ⅓ of the volume. The residue was acidified with 6N HCl, and was extracted into ethyl acetate. The solids isolated from the ethyl acetate layer were triturated with acetone to yield 1-ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (696 mg, 79%) as a light orange solid.

Step B: 1-Ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (600 mg, 2.43 mmol) was suspended in a solution of CH₂Cl₂ (27 ml) and DMF (20 μL). Oxalyl chloride (470 μL, 5.38 mmol) was added, and the reaction mixture was stirred for 1 hour at room temperature. This mixture was then slowly poured into a rapidly stirring solution of concentrated NH₄OH (10 mL). This was then partitioned in H₂O and EtOAc. The residue from the ethyl acetate layer was triturated with acetone to yield 6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide (511 mg, 85%) as a white solid.

Step C: A mixture of 150 mg (0.61 mmol) of 6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide in diglyme (3.6 mL), and bromoacetaldehyde dimethyl acetal (430 μL, 3.7 mmol) was heated at 125° C. for 2 h. The reaction mixture was cooled and partitioned in H₂O and EtOAc. The organic phase was dried and concentrated and the product was purified by silica gel chromatography (EtOAc/CH₂Cl₂ 5-10%). The product containing fractions were combined and concentrated and the solid was triturated with hexanes to yield methyl 1-ethyl-3-oxazol-2-yl-1H-indole-6-carboxylate (75 mg, 46%) as a yellow solid.

Example 1R Preparation of 1-ethyl-6-methoxy-3-thiazol-2-yl-1H-indole (compound 73)

Step A: 1-Ethyl-6-methoxy-1H-indole (900 mg, 5.14 mmol) was dissolved in DMF (1.5 mL). This was added dropwise to an ice-cold solution of POCl₃ (500 μL, 5.2 mmol) in DMF (1.75 ml). After stirring at room temperature for 90 minutes, the reaction mixture was re-cooled in an ice bath and was slowly quenched with 6N NaOH (4 mL). The reaction mixture was partitioned between EtOAc and H₂O. Purification by silica gel chromatography (EtOAc/CH₂Cl₂, 5/95) yielded 1-ethyl-6-methoxy-1H-indole-3-carbaldehyde (849 mg, 81%) as a yellow solid.

Step B: 1-Ethyl-6-methoxy-1H-indole-3-carbaldehyde (600 mg, 2.95 mmol) was dissolved in acetone (85 mL). A solution of KMnO₄ (450 mg, 2.85 mmol) in H₂O (28 mL) was added. This was stirred at room temperature for 5 hours. Another solution of KMnO₄ (450 mg, 2.85 mmol) in H₂O (25 mL) was then added. After stirring for another hour at room temperature, the reaction was complete. The reaction mixture was quenched with 10% H₂O₂ (1.5 mL), and was then filtered through celite. The filtrate was stripped down under vacuum to roughly ⅓ of the volume. The residue was acidified with 6N HCl, and was extracted into ethyl acetate. Purification by silica gel column (hexanes/acetone/acetic acid, 70/30/1) yielded crude product. Trituration with ether yielded pure 1-ethyl-6-methoxy-1H-indole-3-carboxylic acid (365 mg, 56%) as a yellow solid.

Step C: 1-Ethyl-6-methoxy-1H-indole-3-carboxylic acid (250 mg, 1.14 mmol) was suspended in a solution of CH₂Cl₂ (12.5 mL) and DMF (10 μL). Oxalyl chloride (230 μL, 2.64 mmol) was added, and the reaction mixture was stirred for 1 hour at room temperature. This mixture was then slowly poured into a rapidly stirring solution of concentrated NH₄OH (5 mL). This was then partitioned in H₂O and EtOAc. The residue from the ethyl acetate layer was triturated with acetone to yield 1-ethyl-6-methoxy-1H-indole-3-carboxamide (134 mg, 54%) as a white solid.

Step D: 1-Ethyl-6-methoxy-1H-indole-3-carboxamide (120 mg, 0.55 mmol), Lawesson's reagent (240 mg, 0.6 mmol), and toluene (2 mL) were heated at 90° C. for 90 min. The reaction mixture was concentrated and purified by silica gel chromatography (EtOAc/CH₂Cl₂, 1/9) to yield 1-ethyl-6-methoxy-1H-indole-3-thiocarboxamide as a yellow solid (92 mg, 71%).

Step E: 1-Ethyl-6-methoxy-1H-indole-3-thiocarboxamide (83 mg, 0.36 mmol), glyme (3.6 mL) and bromoacetaldehyde dimethyl acetal (220 μL, 1.86 mmol) were heated at 80° C. for 16 h. More bromoacetaldehyde dimethyl acetal (250 μL was added. This was heated at 80° C. for 2 h. Addition of 250 μL more bromoacetaldehyde dimethyl acetal was followed by heating for another 2 hours. The reaction mixture was cooled to room temperature, absorbed onto silica and purified by silica gel chromatography (hexanes/EtOAc, 7/3) to afford 1-ethyl-6-methoxy-3-thiazol-2-yl-1H-indole as a brown oil (44 mg, 47%).

The following compounds were prepared following the procedure described above: Compounds 78, 101, 104, 105 and 106.

Example 1S Preparation of 1-ethyl-6-methoxy-2-phenoxymethyl-1H-indole-3-carbonitrile (compound 99)

Step A: To a suspension of LiAlH₄ (7.6 g, 0.2 mol) in dioxane (100 mL) was added dropwise a solution of methyl 6-methoxy-1H-indole-2-carboxylate (8.2 g, 0.04 mol) in dioxane (50 mL) at 0° C. After the addition, the mixture was stirred at room temperature for 1 h and then heated at reflux for 5 h. After cooling to 0° C., the reaction was quenched by water (dropwise) and then 15% aqueous NaOH. After stirring at room temperature for 1 h, the mixture was filtered through Celite. The solid was washed with large amount of EtOAc. The solvent was washed with brine, dried over Na₂SO₄ and evaporated under vacuum. The residue was purified by flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 61% of 6-methoxy-2-methyl-1H-indole.

Step B: To a solution of 6-methoxy-2-methyl-1H-indole (3.9 g, 24 mmol) in acetonitrile (200 mL) and DMF (20 mL) was added dropwise a solution of C1SO₂NCO (4 mL, 1.3 eq.) in acetonitrile (31 mL) at 0° C. After the addition, the mixture was stirred at room temperature for 3 h. Then it was poured into ice water and saturated NaHCO₃ was added to it until it became basic. The aqueous phase was extracted with CH₂Cl₂ and then evaporated. The residue was purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 81% of 6-methoxy-2-methyl-1H-indole-3-carbonitrile.

Step C: To a suspension of NaH (0.6 g, 2 eq.) in DMF (7 mL) was added a solution of 6-methoxy-2-methyl-1H-indole-3-carbonitrile (1.3 g, 7.0 mmol) in DMF (8 mL) followed by ethyl iodide (1.2 mL, 2 eq.) at 0° C. After stirring for 1 h, the mixture was poured into ice water and the extracted with CH₂Cl₂. The organic layer was washed with brine and dried with Na₂SO₄. The solvent was evaporated under vacuum and purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 92% of 1-ethyl-6-methoxy-2-methyl-1H-indole-3-carbonitrile.

Step D: To a solution of 1-ethyl-6-methoxy-2-methyl-1H-indole-3-carbonitrile (1.38 g, 6.45 mmol) in benzene (130 mL) was added benzoyl peroxide (226 mg) and NBS (1.21 g, 1.05 eq.). Then the mixture was heated to reflux for 3 h. After cooling and filtering, the filtrate was concentrated under vacuum. The crude 2-bromomethyl-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.6 g, 86%) was used without further purification.

Step E: To a solution of NaH (44 mg, 4 eq.) in DMF (0.5 mL) was added 2-bromomethyl-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (80 mg, 0.274 mmol) and phenol (2 eq.). After stirring for 20 h, the mixture was poured into ice water and extracted with CH₂Cl₂. The organic layer was washed with brine and dried with Na₂SO₄. The solvent was evaporated under vacuum and purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 1-ethyl-6-methoxy-2-phenoxymethyl-1H-indole-3-carbonitrile, compound 99.

Example 1T Preparation of 6-nitro-2-pyrrol-1-yl-1H-indole-3-carbonitrile (compound 7)

Step A: A solution of 2-fluoro-5-nitroaniline (11.7 g, 74.9 mmol) in dimethylformamide (120 mL) was treated with malononitrile (5.28 g, 80.0 mmol) and potassium carbonate (11.05 g, 80.0 mmol) (Modification of Chem. Heterocyclic Cpd. (Engl. Trans., 9, 37 (2001). The resulting heterogeneous mixture was heated to gentle reflux for 3 h, then cooled and poured into water (500 mL). The resulting precipitate was collected by filtration and taken up into ethyl acetate (300 mL). This solution was dried over Na₂SO₄, filtered and partially evaporated to give a precipitate, which was collected by filtration. Further evaporation and filtration gave a second crop. The two crops were combined and dried under vacuum to give 2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile (7.90 g, 52%) as an orange powder.

Step B: A solution of 2-amino-6-nitro-1H-indole-3-carbonitrile (362 mg, 1.79 mmol) in acetic acid (5 mL) was treated with 2,5-dimethoxytetrahydrofuran (0.30 mL, 2.27 mmol), and the solution was heated to reflux for 14 h. After cooling to ambient temperature, the solution was poured into water (100 mL), and solid sodium bicarbonate was added until CO₂ evolution ceased. The mixture was extracted with EtOAc (2×100 mL), and the extracts were washed with saturated brine, combined, dried over MgSO₄, filtered and concentrated. The residual material was separated by silica gel chromatography (EtOAc/hexanes, 1/4) to afford 6-nitro-2-pyrrol-1-yl-1H-indole-3-carbonitrile, compound 5, as a yellow solid (232 mg, 51%).

Example 1U Preparation of N-(3-cyano-1-ethyl-6-nitro-1H-indol-2-yl)acetamide (compound 25)

Step A: Sodium hydride (42 mg, 1.05 mmol, 60% w/w suspension in mineral oil) was washed with hexane and taken up in dimethylsulfoxide (1 mL). A solution of 2-amino-6-nitro-1H-indole-3-carbonitrile, prepared in procedure 1T) in dimethylsulfoxide (1 mL) was added by syringe, and the resulting mixture was stirred for 20 min. Then, iodoethane (77 μL, 0.96 mmol) was added by syringe, and the mixture was stirred for 14 h. The reaction was then poured into EtOAc (50 mL), and this solution was washed with water (3×50 mL) and saturated brine (40 mL). The aqueous phases were back-extracted with EtOAc, and the organic extracts were combined, dried over Na₂SO₄, filtered and evaporated. The residual material was separated by column chromatography over silica gel (EtOAc/hexanes, 1/1) to afford first a small amount of a dialkylated analog, then the desired compound, 2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile (114 mg, 52%), and finally unreacted starting material. The desired product was isolated as an orange powder.

Step B: Sodium hydride (44 mg, 1.10 mmol, 60% w/w in mineral oil) was washed with hexanes and suspended in 1,4-dioxane (3 mL). A solution of 2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile (120 mg, 0.521 mmol), prepared in step B, above, in dioxane (2 mL) was added, and the resulting mixture was allowed to stir for 30 min. Then, acetyl chloride (45 μL, 0.63 mmol) was added by syringe, and the solution was stirred for an additional 12 h. The reaction was partitioned between water and EtOAc (20 mL each), and the organic phase was washed with brine. The aqueous phases were back-extracted in sequence with ethyl acetate, and the organic extracts were combined, dried over MgSO₄, filtered and evaporated. The resulting solid was triturated with Et₂O, collected by filtration and dried under vacuum to afford N-(3-cyano-1-ethyl-6-nitro-1H-indol-2-yl)-acetamide (100 mg, 71%), compound 25, as an off-white powder.

Using this procedure and substituting the appropriate acid chlorides or chloroformates gave the following compounds: Compounds 23, 26, 35, 36, 203, 204, 214, 215, 216.

Example 1V Preparation of N-ethyl-3-phenyl-5-nitroindole (compound 41)

Step A: To a solution of 5-nitroindole (5.00 g, 30.8 mmol) in pyridine (200 mL) at −4° C. was added a solution of pyridinium bromide perbromide (10.99 g, 34.3 mmol) in pyridine (200 mL) dropwise under nitrogen with stirring. After complete addition, the reaction mixture was stirred for 5 min at 0° C. The reaction mixture was diluted in 0° C. water (200 mL) and extracted with 200 mL of Et₂O. The organic layer was washed with 6 M HCl (300 mL), 5% NaHCO₃ (300 mL), and brine (300 mL). The organic phase was dried over MgSO₄ and solvent was removed to give 3-bromo-5-nitroindole as a yellow powder, 80% pure with 20% 5-nitroindole (6.80 g, 74% yield).

Step B: A solution of 3-bromo-5-nitroindole from above (625 mg, 2.1 mmol), phenylboronic acid (381 mg, 3.13 mmol), triphenylphosphine (109.3 mg, 0.417 mmol) in dimethoxyethane (4.16 mL) was degassed. To this mixture 2N sodium carbonate (6.25 mL) was added, and reaction mixture was degassed again. To the reaction was added palladium (II) acetate (23.4 mg, 0.104 mmol), and the reaction was refluxed under dry nitrogen with stirring for 8 hours. The reaction mixture was then diluted with 1 M HCl (100 mL), and extracted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL), and brine (100 mL). The organic phase was dried over MgSO₄ and concentrated in vacuo. The crude product was purified by chromatography over silica gel (EtOAc/hexanes, 10/90) to afford 3-phenyl-5-nitroindole as an orange powder (45 mg, 9% yield).

Step C: To a mixture of 60% NaH in mineral oil (8.7 mg, 0.630 mmol) and DMF (1.0 mL) was added dropwise a solution of 3-phenyl-5-nitroindole (40.0 mg, 2.1 mmol) in DMF (0.75 mL). The reaction mixture was stirred for 20 min at 0° C. under N₂. Ethyl iodide (14.8 μL, 0.185 mmol) was added dropwise and the reaction mixture was stirred for an additional 3 hours. The reaction mixture was diluted with water (250 mL), and extracted with EtOAc (30 mL). The organic phase was washed with water (250 mL) and was then dried over MgSO₄ and the solvent was removed in vacuo. The desired N-ethyl-3-phenyl-5-nitroindole was obtained as a yellow powder (40.0 mg, 89.5% yield).

In similar fashion the following compound was prepared: Compound 40

Example 1W Preparation of [3-Cyano-1-(4-methoxyphenyl)-1H-indol-6-yl]-carbamic acid propyl ester (compound 97)

6-Amino-1-(4-methoxyphenyl)-1H-indole-3-carbonitrile (30 mg, 0.12 mmol), was suspended in EtOH (300 μL). Propyl chloroformate (168 μL, 1.5 mmol) was added, and this mixture was stirred at room temperature overnight. The addition of triethylamine (300 μL), followed by another hour of stirring at room temperature, completed the reaction. This reaction mixture was loaded directly onto a silica column, and was eluted with CH₂Cl₂. Another silica column (3/2, ether/hexanes) was needed to fully purify the product, [3-cyano-1-(4-methoxy-phenyl)-1H-indol-6-yl]-carbamic acid propyl ester (19 mg, 45%), as a white solid.

Example 1X Preparation of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-methanesulfonamide (compound 130)

2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.16 mmol), prepared as described by the method of Example 1H, was dissolved in pyridine (550 μL) at room temperature. Methanesulfonyl chloride (17 μL, 0.21 mmol) was added dropwise. This was stirred overnight at room temperature. The reaction mixture was then diluted in ethyl acetate and was washed with aqueous HCl, followed by brine. The organic layer was dried and concentrated. Purification by silica gel chromatography (9/1, CH₂Cl₂/EtOAc) yielded N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-methanesulfonamide (58 mg, 92%) as an off-white solid.

The following compounds were made using the procedure shown above, by substituting the appropriate aminophenylethynyl indoles and sulfonyl chlorides: Compounds 131, 132, 208, 209, and 210.

Example 1Y Preparation of N-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-methanesulfonamide (compound 129)

A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in Example 1Ga, step B in THF (3 mL) was cooled to 0° C. and treated with triethylamine (0.04 mL, 0.31 mmol) and methanesulfonylchloride (0.02 mL, 0.29 mmol) at stirred, warming to room temperature overnight. The reaction mixture was then diluted with H₂O and extracted with ethyl acetate (3×). The organic phase was washed with H₂O and saturated NaCl, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-50%) to afford 60 mg (68%) of N-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-methanesulfonamide as a tan solid.

Using essentially the same procedure as above and substituting the appropriate aminophenylindole and sulfonyl chloride or carrying out the reaction in pyridine as both base and solvent gave the following compounds: 83, 85, 86, 87, 88, 243, 251, 252, 272, 273, 287, 289, 365, 366, 367, 368, 369, 370, 371, 394, 439, 440, 448, 449, 451, 452, 477, 487, 488, 495, 505, 510, 548, 549, 550, 551, 552, 562, 563, 598, 599, 601, 602, 608, 609, 610, 615, 616, 617, 621, 622, 623, 629, 630, 631, 639, 655, 657, 658, 662, 669, 670, 671, 674, 675, 701, 702, 703, 706, 707, 708, 709, 710, 711, 713, 715, 720, 789, 790, 791, 850, 851.

Example 1Za Preparation of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-acetamide (compound 138)

2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (95 mg, 0.29 mmol), prepared as described in Example 1H, was dissolved in THF (1.4 mL). Triethylamine (84 μL, 0.6 mmol) was added, followed by dropwise addition of acetyl chloride (44 μL, 0.5 mmol). This was stirred at room temperature for 1 h. The reaction mixture was partitioned between H₂O and EtOAc. The organic layer was dried and concentrated. Purification by silica chromatography (9/1, CH₂Cl₂/EtOAc) yielded N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-acetamide (103 mg, 96%) as a yellow solid.

The following compounds were prepared by the procedure shown above, substituting the appropriate aminophenylethynyl indoles and acid chlorides: Compounds 82, 139, 152, 153, 162, 163, 165, 167, 205, 206, 207, 211, 212, 213, 219, 224, 225, 228.

Example 1Zb Preparation of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-formamide (compound 241)

Acetic anhydride (2.5 mL) and 98% formic acid (1.0 mL) were heated at 65° C. for 1 hour. This was cooled to 0° C. 2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as in example 1H, was taken up in THF (1.2 mL) and added to the formic acetic anhydride mixture. This was stirred at 0° C. for 30 minutes. The reaction mixture was then partitioned between H₂O and EtOAc. The EtOAc layer was washed with saturated NaHCO₃, followed by saturated brine. The organic layer was dried and concentrated. Purification by silica gel chromatography (4/1, CH₂Cl₂/EtOAc) yielded of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-formamide (105 mg, 96%) as a yellow solid.

The following compound was prepared similarly as described above: Compound 218.

Example 1AA Preparation of N-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-acetamide (compound 128)

A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in Example 1Ga, step B in THF (3 mL) was cooled to 0° C. and treated with triethylamine (0.04 mL, 0.31 mmol) and acetyl chloride (0.02 mL, 0.29 mmol) and stirred, warming to room temperature overnight. The reaction mixture was then diluted with H₂O and extracted with ethyl acetate (3×). The organic phase was washed with H₂O and saturated NaCl, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-50%) to afford 57 mg (71%) of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]acetamide as a tan solid.

Using essentially the same procedure as above and substituting appropriate aminophenyl indoles and the acid chlorides, the following compounds were prepared: Compounds 81, 242, 244, 324, 325, 326, 327, 328, 329, 330, 383, 420, 421, 422, 423, 424, 425, 544, 558, 559, 560, 561, 565, 566 567, 644, 645, 646, 755, 756, 757, 759, 760, 761, 762, 763, 764, 765, 766, 798, 799, 801, 802, 803, 804, 854, 855, 856, 857, 858, 859.

Example 1AB Preparation of 1-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)phenyl]-3-ethyl urea (compound 220)

2-(3-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, was dissolved in pyridine (670 μL). Ethyl isocyanate (62 μL, 0.75 mmol) was added. The reaction mixture was then heated at 100° C. for 2 h. The mixture was then diluted in EtOAc, and was washed with aqueous HCl, followed by brine. The organic layer was dried and concentrated. Purification by silica chromatography (4/1, CH₂Cl₂/EtOAc), followed by trituration with hexanes/acetone (1/1), yielded 1-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-3-ethyl urea (44 mg, 36%) as a white solid.

Example 1AC Preparation of 1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea (compound 156)

2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, was suspended in toluene (600 μL). 2-Chloroethyl isocyanate (32 μL, 0.37 mmol) was added, and the mixture was heated at 100° C. for 5 h. The reaction mixture was then cooled, diluted in acetone, and absorbed onto silica. Purification by column chromatography (5-10% EtOAc in CH₂Cl₂) yielded 1-(2-chloro-ethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea (73 mg, 54%) as a yellow solid.

The following compounds were prepared using the procedure above: Compound 221.

Example 1AD Preparation of Ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]methyl amide (compound 157)

N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)phenyl]ethanesulfonamide (70 mg, 0.17 mmol), prepared as in Example 1X, was combined with K₂CO₃ (49 mg, 0.35 mmol), and DMF (1.0 mL). Iodomethane (16 μL, 0.26 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted in EtOAc, and was washed with H₂O and then brine. The organic layer was dried and concentrated. Purification by silica chromatography (95/5, CH₂Cl₂/EtOAc) yielded a light tan solid. Trituration gave ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]methyl amide (61 mg, 85%) as an orange-white solid.

The following compounds were prepared using the procedure above, substituting the appropriate sulfonamide: Compound 182, 652, 840.

Example 1AE Preparation of 1-ethyl-5-methoxy-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-carbonitrile (compound 245)

Step A: Methyl 4-(3-cyano-1-ethyl-5-methoxy-1H-indol-2-yl)-benzoate (350 mg, 1.05 mmol), prepared as described in Example 1Ga step B, was combined with NaOH (40 mg, 1 mmol), H₂O (0.8 mL), and THF (3.4 mL) and was heated at 80° C. for 1 hour. The reaction mixture was diluted in H₂O and was then ether-washed. The aqueous layer was acidified with aqueous HCl, and was extracted into EtOAc. The organic layer was dried and concentrated to yield 4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (311 mg, 92%) as a pure white solid.

Step B: 4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (50 mg, 0.16 mmol) was suspended in CH₂Cl₂ (2.2 mL) and catalytic DMF (2 μL). Oxalyl chloride (22 μL, 0.25 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, at which time full dissolution occurred. This reaction mixture was pipetted dropwise into a vigorously stirring solution of morpholine (1.0 mL) in CH₂Cl₂ (5 ml). After addition was complete, the reaction mixture was washed with aqueous HCl solution. The organic layer was dried and concentrated. Purification by silica column (1:1 CH₂Cl₂/EtOAc) yielded 1-ethyl-6-methoxy-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-carbonitrile (56 mg, 90%) as a white solid.

The following compounds were prepared similarly as described above: Compounds 113, 114, 246, 270, 271 290, 291, 292, 323, 377, 378, 379, 380, 381, 382, 384, 385, 386, 387, 388, 389, 390, 391, 392, 432, 433, 564, 568, 569, 570, 571, 572, 573, 647, 648, 853, 860, 861, 862.

Example 1AF Preparation of cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-ylethynyl)-phenyl]amide (compound 194)

Cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-amide (60 mg, 0.16 mmol), prepared as described in Example 1Za, was stirred in BBr₃ (800 μL, 1M in CH₂Cl₂, 0.8 mmol) at room temperature for 1 hour. The reaction mixture was quenched with H₂O, and was extracted with CH₂Cl₂. The organic layer was dried and concentrated. Purification by silica chromatography (EtOAC) gave impure product. These crude product was triturated with 1/1 hexanes/acetone to yield cyclopropanecarboxylic acid [4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-ylethynyl)-phenyl]-amide (32 mg, 54%) as an off-white solid.

The following compounds were prepared using the procedure above, substituting the appropriate sulfonamides (from Example 1×) or amides (from Example 1Z): Compounds 164, 168, 183, 193, 195.

Example 1AG Preparation of 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenylethynyl]-1H-indole-3-carbonitrile (compound 166)

1-(2-Chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea (55 mg, 0.13 mmol), prepared as in Example 1AC, was combined with K₂CO₃ (50 mg, 0.36 mmol) and DMF (550 μL). This mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted in EtOAc, and was washed with H₂O, and then with brine. The organic layer was dried and concentrated. Purification by silica chromatography (10-50%, EtOAc/CH₂Cl₂) yielded 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenylethynyl]-1H-indole-3-carbonitrile (47 mg, 94%) as a white solid.

The following compounds were prepared using the above procedure, substituting the appropriate urea: Compound 222.

Example 1AH Preparation of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-dimethylphosphinic amide (compound 227)

2-(3-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, was dissolved in pyridine (300 μL) at 0° C. Dimethylphosphinic chloride (60 mg, 0.53 mmol) in THF (300 μL) was added. The reaction was stirred at room temperature for 2 hours. The reaction mixture was diluted in EtOAc, and was washed with aqueous HCl followed by brine. The organic layer was dried and concentrated. Purification by silica chromatography (acetone) yielded N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-dimethylphosphinic amide (65 mg, 52%), compound 227, as a pure white solid. The silica column was then flushed with 9/1 CH₂Cl₂/MeOH to yield 9 mg of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-bis-(dimethylphosphinic) amide as a by-product.

Example 1AI Preparation of 1-ethyl-6-methoxy-3-[5-(4-methoxyphenyl)-isoxazol-3-yl]-1H-indole (compound 116)

Step A: A mixture of 1-ethyl-6-methoxy-1H-indole-3-carbaldehyde oxime (0.20 g, 0.92 mmol), prepared from the aldehyde precursor in example 1R, in dichloroethane (3 mL) was treated with N-chlorosuccinimide (0.12 g, 0.92 mmol) and pyridine (0.04 mL, 0.46 mmol) and stirred at room temperature for 1 h. The reaction mixture was then poured into H₂O and acidified with 1N HCl until the pH was 2. The mixture was extracted with EtOAc and the organic phases were washed with H₂O and saturated NaCl and dried and concentrated to a mixture of chlorooximes, which were used in the next step without further purification.

Step B: The mixture of chlorooximes prepared above was dissolved in CH₂Cl₂ (5 mL) and to this was added 4-methoxyphenylacetylene (0.24 g, 1.84 mmol) and triethylamine (0.25 mL, 1.84 mmol) at 0° C. and the reaction was then stirred overnight warming to room temperature. The reaction was then diluted with H₂O and extracted with EtOAc (3×). The organic phases were washed with H₂O and saturated NaCl and dried and concentrated. Chromatography over silica gel (EtOAc/hexanes, 10-20%) gave 76 mg (24%) of 1-ethyl-6-methoxy-3-[5-(4-methoxy-phenyl)-isoxazol-3-yl]-1H-indole as a tan solid.

Example 1AJ Preparation of [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (compound 121)

A biphasic mixture of 2-(4-amino-phenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in example 1Ga step B, and ethyl chloroformate (0.03 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO₃ (3 mL) was prepared at 0° C. and then allowed to warm to room temperature and stirred for 24 h. The reaction was then diluted with H₂O and extracted with EtOAc (2×). The organic phases were washed with H₂O and saturated NaCl and then dried and concentrated. Flash chromatography (EtOAc/hexanes 20-40%) gave 48 mg (55%) of [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester as an off-white solid.

The following compound was prepared in similar fashion: Compound 122, 293, 294, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 372, 434, 435, 450, 453, 454, 455, 457, 485, 486, 489, 490, 500, 501, 502, 503, 506, 507, 508, 509, 545, 546, 547, 553, 554, 555, 556, 557, 581, 582, 583, 584, 585, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 603, 604, 605, 606, 607, 618, 619, 624, 625, 637, 640, 641, 664, 665, 676, 677, 721, 722, 723, 734, 735, 736, 737, 738, 739, 744, 745, 746, 747, 787, 788, 792, 793, 794, 795, 796, 797, 819, 822, 823, 824, 825, 826, 849.

Example 1AK Preparation of 1-ethyl-5-thiophen-3-yl-1H-indole-3-carbonitrile (compound 141)

A tube was charged with a mixture of 5-bromo-1-ethyl-1H-indole-3-carbonitrile (100 mg, 0.40 mmol), thiophene-3-boronic acid (72 mg, 0.56 mmol), PdCl₂(PPh₃)₂ (11 mg, 0.016 mmol) and CsF (152 mg, 1 mmol) and then alternately evacuated and filled with nitrogen (3×) and diluted with dimethoxyethane (3 mL) and then heated to 90° C. for 19 h. After cooling, the crude reaction mixture was diluted with saturated NaHCO₃ and extracted with EtOAc (2×). The combined organic phases were washed with saturated NaCl and dried and concentrated. Flash chromatography over silica gel (CH₂Cl₂/hexanes, 40/60) gave 25 mg (25%) of 1-ethyl-5-thiophen-3-yl-1H-indole-3-carbonitrile as a white solid.

The following compounds were prepared in similar fashion: Compounds 140 and 142.

Example 1AL Preparation of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-methyl methanesulfonamide (compound 180)

A solution of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (130 mg, 0.35 mmol), prepared as in Example 1Y, in DMF (10 mL) was treated with NaH (21 mg, 0.53 mmol), and stirred at room temperature for 10 min. Iodomethane (0.03 mL, 0.53 mmol) was added, and the mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with H₂O, and extracted with EtOAc (2×). The organic phases were washed with H₂O and saturated NaCl and then dried and concentrated. Purification by flash chromatography over silica gel (EtOAc/CH₂Cl₂, 0-1%) gave 60 mg (45%) of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-methyl methanesulfonamide as a white solid.

In similar fashion the following compounds were prepared: Compounds 181, 642, 643, 672, 673, 816, 852.

Example 1AM Preparation of N-[4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-methanesulfonamide (compound 189)

A solution of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (85 mg, 0.23 mmol) in CH₂Cl₂ (2 mL) was cooled to −5° C. A solution of boron tribromide (1.15 mL, 1.15 mmol, 1M solution in CH₂Cl₂) was added and the reaction mixture was allowed to warm to 10° C. over 4 h. The reaction mixture was poured into H₂O and extracted with EtOAc (3×). The combined organic phases were washed with H₂O and saturated NaCl and dried and concentrated. Chromatography over silica gel (EtOAc/CH₂Cl₂, 5-10%) gave 18 mg (22%) of N-[4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]methanesulfonamide as a tan solid.

The following compounds were made similarly: Compounds 190, 191, 192.

Example 1AN Preparation of methyl 3-[5-(3-cyano-6-methoxy-1H-indol-2-yl)-[1,2,4]oxadiazol-3-yl]benzoate (compound 226)

Step A: To a mixture of 6-methoxy-1H-indole-3-carbonitrile (5.88 g, 40 mmol), prepared as described in the previous examples, and (Boc)₂O (9.59 g, 44.0 mmol) in DCM (50 mL) was added DMAP (0.10 g, 0.8 mmol). The mixture was stirred at room temperature for 48 h, then treated with water (30 mL) and dried over anhydrous Na₂SO₄. The crude product was chromatographed over silica gel (hexanes/EtOAc, 7/1) to furnish the desired intermediate, 3-cyano-6-methoxyindole-1-carboxylic acid tert-butyl ester (8.48 g, 86%).

Step B: The above intermediate (2.72 g, 10.0 mmol) was dissolved in anhydrous THF (20 mL), and cooled at −78° C., followed by the addition of LDA (1.5 M monoTHF in cyclohexane, 10.0 mL, 15 mmol). After stirring for 45 min, CO₂ gas was introduced for 2 h. The mixture was then brought to room temperature and the solvent was removed in vacuo, and the residue was treated with water and acidified to pH=2 with 6 N HCl. The precipitate was collected and washed with water and dried to provide the acid intermediate, 3-cyano-6-methoxy-indole-1,2-dicarboxylic acid 1-tert-butyl ester (2.40 g, 73%).

Step C: To a solution of 3-cyano-6-methoxyindole-1,2-dicarboxylic acid 1-tert-butyl ester (474 mg, 1.5 mmol) prepared above, and HOBt (200 mg, 1.5 mmol) in DCE/DMF (10 mL/1 mL), was added DCC (310 mg, 1.5 mmol), followed by 3-(N-hydroxycarbamimidoyl)benzoic acid methyl ester (291 mg, 1.5 mmol). The mixture was stirred at room temperature for 2 h and filtered. The filtrate was collected and the solvent was replaced with chlorobenzene, followed by the heating at 150° C. for 48 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was chromatographed (silica gel, CH₂Cl₂/EtOAc, 8/2) to furnish the intermediate, 3-cyano-6-methoxy-2-[3-(3-methoxycarbonylphenyl)-[1,2,4]oxadiazol-5-yl]-indole-1-carboxylic acid tert-butyl ester, which was treated with 50% TFA in DCM (10.0 mL) at room temperature for 1 h. After removal of the volatiles in vacuo, the residue was suspended in water and neutralized with K₂CO₃ to provide the desired product, methyl 3-[5-(3-cyano-6-methoxy-1H-indol-2-yl-)[1,2,4]oxadiazol-3-yl]benzoate, compound 226 (350 mg, 62%).

Example 1AO Preparation of 1-ethyl-2-(4-methanesulfonylphenyl)-6-methoxy-1H-indole-3-carbonitrile (compound 265)

A solution of 1-ethyl-6-methoxy-2-(4-methylsulfanylphenyl)-1H-indole-3-carbonitrile (0.12 g, 0.37 mmol) in CH₂Cl₂ (5 mL) was treated with m-chloroperbenzoic acid (Aldrich, <77%, 0.26 g,) in one portion and the reaction was stirred for 10 h at room temperature. The reaction was then diluted with H₂O and saturated NaHCO₃ and extracted twice with EtOAc. The organic phases were washed with NaHCO₃ (2×) and saturated NaCl and dried and concentrated to a dark semi-solid. The crude product was purified by flash chromatography (EtOAc/CH₂Cl2, 0-3%) through a 5 gram silica cartridge topped with 1 gram of basic alumina to give 72 mg (55%) of 1-ethyl-6-methoxy-2-(4-methylsulfanylphenyl)-1H-indole-3-carbonitrile as an off-white solid.

Example 1AP Preparation of N-{4-[3-cyano-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-phenyl}methanesulfonamide (compound 478)

A solution of N-{4-[6-(2-chloroethoxy)-3-cyano-1-ethyl-1H-indol-2-yl]-phenyl}methanesulfonamide (90 mg, 0.21 mmol), morpholine (0.06 mL, 0.65 mmol), NaI (32 mg, 0.21 mmol) and diisopropyl ethylamine (0.06 mL, 0.32 mmol) in CH₃CN (2 mL) was heated in a sealed tube at 100° C. for 25 h. The reaction mixture was cooled to room temperature, diluted with H₂O and extracted with EtOAc (3×). The combined organic phases were washed with saturated NaCl, dried and concentrated. The crude solid was triturated with EtOAc and filtered to give 41 mg (41%) of N-{4-[3-cyano-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-phenyl}methanesulfonamide as a tan solid.

The following compounds were made similarly: Compounds 479, 480, 481, 482, 496, 497 and 498.

Example 1AQ Preparation of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide (compound 653)

Step A: A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, prepared by example 1Ga step B, (0.82 mg, 2.82 mmol), in pyridine (10 mL) was treated dropwise with chloroethyl sulfonylchloride (0.38 mL, 3.66 mmol) at room temperature. After stirring for 4 h, the reaction mixture was quenched with ice-water and enough 6N HCl was added until the pH was lowered to 2. The suspension was extracted with hot EtOAc (3×). The organic phases were then washed sequentially with 1N HCl, H₂O and saturated NaCl and dried and concentrated to give ethenesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide as a pale orange solid which was used directly in the next step without further purification.

Step B: A suspension of ethenesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide, prepared above, (70 mg, 0.18 mmol), morpholine (0.05 mL, 0.55 mmol) in CH₃CN (1.5 mL) was heated at reflux for 1.5 h. After cooling to room temperature, the reaction was concentrated and the residue was purified by flash chromatography (acetone/EtOAc, 2/98) over silica gel to afford 89 mg (100%) of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide as a tan foam.

The following compound was made similarly: Compound 654.

Example 1AR Preparation of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methyl amide (compound 668)

A solution of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1-indol-2-yl)-phenyl]amide, prepared in example 1AQ (60 mg, 0.13 mmol) in DMF (3 mL) was treated with K₂CO₃ (35 mg, 0.26 mmol) and methyl iodide (0.02 mL, 0.26 mmol). After stirring at room temperature for 1.5 h, the reaction mixture was diluted with H₂O and extracted with EtOAc (2×). The organic phases were then washed with H₂O (3×) and saturated NaCl, and then dried and concentrated to afford a residue. Flash chromatography over silica gel (acetone/EtOAc, 0-2%) gave 31 mg (50%) of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methyl amide as an off white solid.

The following compounds were made similarly: Compounds 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698.

Example 1AS Preparation of 2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (compound 84)

Step A: A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, prepared by example 1Ga step B, (2.78 g, 9.55 mmol) in pyridine (40 mL) was treated dropwise with 3-chloropropanesulfonyl chloride (1.45 mL, 11.9 mmol) and the reaction was stirred for 4 h at room temperature. The reaction was diluted with water and enough 6N HCl to lower the pH to 2. The reaction mixture was extracted with EtOAc (3×) and the combined organic layers were washed sequentially with 1N HCl, water and saturated NaCl and then dried and concentrated to give 3.9 g (95%), of 3-chloropropane-1-sulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide as a brown foam which was used directly in the next step.

Step B: A solution of 3-chloropropane-1-sulfonic acid [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]amide, prepared above (3.65 g, 2.33 mmol) in DMF (100 mL) was treated with K₂CO₃ and heated at 70° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with H₂0 and extracted 3× with hot EtOAc. The hot organic layers were washed with warm H₂0 (3×) and saturated NaCl and dried and concentrated to a solid. Trituration (CH₂Cl₂/hexanes) gave 2.27 g (68%) of 2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yOphenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile as a light brown solid.

The following compounds were made in similar fashion: Compound 649, 775.

Example 1AT Preparation of 2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (compound 666)

Step A: Following the procedure in example 1B step A, 2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile was treated with 1M BBr₃ solution in CH₂Cl₂ at −15° C. for 1.5 h and then poured into ice-water and filtered and dried to afford 2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrile in nearly quantitative yield.

Step B: Following the procedure in example 1B step B, 2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrile, K₂CO₃, 2-iodopropane and methyl ethyl ketone were heated at reflux to give, after flash chromatography (EtOAc/CH₂Cl₂, 0-2%), 61% of 2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-isopropoxy-1H-indole-3-carbonitrile as an off-white solid.

The following compounds were made similarly: Compounds 667, 699

Example 1AU Preparation of 2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indole-3-carbonitrile (compound 729)

A mixture of 2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrile, prepared in example 1AT above (70 mg, 0.25 mmol), K₂CO₃ (75 mg, 0.51 mmol), sodium iodide (27 mg, 0.18 mmol), 4-(2-chloroethyl) morpholine hydrochloride (42 mg, 0.25 mmol) in methyl ethyl ketone (3 mL) was heated in a sealed tube at 100° C. After 13 hours, DMF (3 mL) was added and the reaction was heated for an additional 6 h. After this time, an additional 42 mg of 4-(2-chloroethyl) morpholine hydrochloride and 135 mg of K₂CO₃ was added and the reaction was heated for an additional 6 h to complete the reaction. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic phases were washed with water (2×) and saturated NaCl and dried and concentrated. Pure 2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indole-3-carbonitrile was obtained by flash chromatography (MeOH/CH₂Cl₂, 0-6%) to give 29 mg (34%) of a tan solid.

The following compounds were made similarly: Compounds 728 and 730.

Example 1AV Preparation of 2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (compound 779)

Step A: A solution of 2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (585 mg, 1.92 mmol) in 10 mL of 1,4-dioxane was treated with ethyl isocyanatoacetate (0.25 mL, 2.12 mmol), and the resulting solution was heated to reflux overnight. The solution was allowed to cool, and the solvent was removed by rotary evaporation. The residual material was triturated with ether, and the resulting precipitate was collected by filtration and dried under vacuum to afford compound 773 (587 mg, 1.35 mmol, 70%).

A similar procedure was used to prepare methyl 2-{3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}-3-phenyl-propionate (compound 777).

Step B: A solution of ethyl {3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}-acetate (compound 773, 101 mg, 0.232 mmol) in THF (10 mL) was treated with a solution of potassium tert-butoxide in tert-butanol (0.30 mL, 1.0 M, 0.30 mmol), and the resulting mixture was allowed to stir overnight. The reaction mixture was partitioned between water and ethyl acetate (50 mL each), and the organic phase was washed with saturated brine. The aqueous phases were extracted with more ethyl acetate, and the extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material was separated by column chromatography (eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford 2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile, compound 779, which was purified further by trituration with ether, collection by filtration and drying under high vacuum (76 mg, 0.196 mmol, 84%).

Example 1AW Preparation of 2-[4-(2,4-dioxo-imidazolidin-1-yl)phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (compound 776)

A solution of 2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (319 mg, 1.04 mmol) in 1,4-dioxane (3 mL) was treated with chloroacetyl isocyanate (0.10 mL, 1.17 mmol), and the resulting solution was warmed to 60° C. overnight. The solution was cooled, and DBU (0.20 mL, 1.31 mmol) was added. This mixture was stirred at ambient temperature overnight, and then was partitioned between water and ethyl acetate (50 mL each). The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material was triturated with ether, and the resulting solid was collected by filtration and dried under high vacuum to afford the title product (319 mg, 0.821 mmol, 79%).

Example 1AX Preparation of N,N-Dimethyl-2-[4-(3,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carboxamide (compound 780) and N,N-Dimethyl-6-ethoxy-1-ethyl-2-[4-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide (compound 781).

Step A. A solution of ethyl {3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}acetate (compound 773, 325 mg, 0.748 mmol), prepared in procedure 1AV, step A, in acetone (5 mL) was treated with HCl (3 mL, 6 N), and the resulting solution was heated to reflux overnight. The reaction mixture was cooled, and the resulting precipitate was collected by filtration, washed with ether and dried under high vacuum to afford the product, 6-ethoxy-1-ethyl-2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide (264 mg, 0.650 mmol, 87%).

Step B. Sodium hydride dispersion in mineral oil (75 mg) was washed with a small portion of hexane, and the hexane layer was decanted off. A solution of 6-ethoxy-1-ethyl-2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide (190 mg, 0.468 mmol) in dimethylformamide (2 mL) was added, and the mixture was stirred for 1 hour. Then, methyl iodide (0.10 mL, 1.61 mmol) was added by syringe. The resulting mixture was allowed to stir at ambient temperature overnight and then was poured into 50 mL of ethyl acetate. The organic phase was washed with water (3×50 mL) and saturated brine (20 mL), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material was separated by column chromatogaphy (1/1 ethyl acetate/hexane, eluting on silica gel 60) to afford the title products, compounds 780 and 781.

Example 1AY Preparation of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-(2-hydroxyethyl)-methanesulfonamide (compound 828)

Step A: Sodium hydride dispersion in mineral oil (108 mg) was washed with a small portion of hexane, and the hexane layer was decanted off. A solution of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (compound 129, 500 mg, 1.35 mmol) in DMF (5 mL) was slowly added. After gas evolution was complete, 2-bromoethyl acetate (0.30 mL, 2.64 mmol) and sodium iodide (20 mg) were added. The mixture was stirred at ambient temperature overnight, and then was poured into 50 mL of ethyl acetate. This was washed with water (3×50 mL) and saturated brine (20 mL), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material was separated by column chromatogaphy (1/1 ethyl acetate/hexane, eluting on silica gel 60) to afford compound 815 (364 mg, 0.799 mmol, 59%).

Step B: A mixture of N-(2-acetoxyethyl)-N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (compound 815, 164 mg, 0.360 mmol) and lithium hydroxide hydrate (45 mg, 1.07 mmol) in 5 mL THF/1 mL water was warmed to 60° C. overnight. The mixture was cooled and poured into ethyl acetate (50 mL). This was washed with water (50 mL) and brine (20 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to afford a solid. The solid was triturated with ether, collected by filtration and dried under high vacuum to afford N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-(2-hydroxyethyl)methanesulfonamide, compound 828 (137 mg, 0.331 mmol, 92%).

Example 1AZ Preparation of 1-ethyl-6-methoxy-2-[4-(2-methoxyethoxy)-phenyl]-1H-indole-3-carbonitrile (compound 248)

1-Ethyl-2-(4-hydroxy-phenyl)-6-methoxy-1H-indole-3-carbonitrile (40 mg, 0.14 mmol), prepared as in example 1Ga step B, was combined with K₂CO₃ (77 mg, 0.56 mmol), bromoethyl methyl ether (26 μL, 0.28 mmol), and DMF (450 μL). This was stirred at room temperature for 1 hour, and then at 75° C. for 3 hours. The reaction mixture was then partitioned between H₂O and EtOAc. The organic layer was dried and concentrated. Purification by silica gel chromatography (CH₂Cl₂, 0-5% EtOAc) to yield 1-ethyl-6-methoxy-2-[4-(2-methoxyethoxy)-phenyl]-1H-indole-3-carbonitrile (44 mg, 90%) as a white solid.

The following compound was prepared similarly as above: Compound 249.

Example 1BA Preparation of 1-ethyl-6-methoxy-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-indole-3-carbonitrile (compound 261)

Step A: 1-Ethyl-6-methoxy-2-[4-(2-hydroxyethoxy)-phenyl]-1H-indole-3-carbonitrile (450 mg, 1.34 mmol), prepared as in example 1AZ, was combined with PPh₃ (878 mg, 3.35 mmol) in CH₂Cl₂ (32 mL) at 0° C. N-bromosuccinimide (600 mg, 3.37 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with aqueous NaHCO₃. The organic layer was dried and concentrated, and purified by silica gel chromatography (CH₂Cl₂) to yield 2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (506 mg, 95%), compound 253 as a white solid.

Step B: 2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (40 mg, 0.1 mmol), prepared as in step A above, was combined with morpholine (50 μL, 0.58 mmol) and acetonitrile (1.0 mL). This was heated at 85° C. for 2 h. The reaction mixture was then partitioned between CH₂Cl₂ and H₂O. The organic layer was dried and concentrated. Purification by silica gel chromatography (6/4, acetone/hexanes) yielded 1-ethyl-6-methoxy-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-indole-3-carbonitrile (39 mg, 96%) as a white solid.

The following compounds were prepared similarly as above, using different amines: Compounds 262, 263, 264.

Example 1BB Preparation of N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-ethyl}methanesulfonamide (compound 268)

Step A: 2-[4-(2-Bromoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (258 mg, 0.65 mmol), prepared in example 1BA, step A, was combined with NaN₃ (144 mg, 2.2 mmol), and MeOH (3.2 mL). This was heated overnight at 75° C. The reaction mixture was then partitioned between CH₂Cl₂ and H₂O. The organic layer was dried and concentrated. Purification by silica gel chromatography (CH₂Cl₂) yielded 2-[4-(2-azidoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (187 mg, 80%), compound 266 as a white solid.

Step B: 2-[4-(2-Azidoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (410 mg, 1.14 mmol), prepared as in step A, above, was suspended in a solution of MeOH (20 mL) and concentrated HCl (500 μL). Pd/C (150 mg, 10%) was added, and this mixture was hydrogenated at 30 p.s.i. for 1 h. This was filtered and the filtrate was concentrated. The filtrate residue was partitioned between EtOAc and 0.5N NaOH. The organic layer was dried and concentrated. Purification by silica gel chromatography (10-30%, MeOH/CH₂Cl₂) yielded 2-[4-(2-aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (298 mg, 78%), compound 267, as a white solid.

Step C: 2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared in step B, above, was dissolved in pyridine (300 μL). Methanesulfonyl chloride (8 μL, 0.1 mmol) was added. This was stirred at room temperature for 45 minutes. More methansulfonyl chloride (4 μL, 0.05 mmol) was added. Stirring continued for another hour. The reaction mixture was partitioned between EtOAc and aqueous HCl. The organic layer was dried and concentrated. Purification by silica gel chromatography (1/1 CH₂Cl₂/EtOAc) yielded N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]ethyl}methanesulfonamide, compound 268 (32 mg, 86%) as a white solid.

The following compound was prepared similarly as above: Compound 269.

Example 1BC Preparation of N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-ethyl}acetamide (compound 274)

2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example 1BB, step B, was dissolved in THF (400 μL), and Et₃N (24 μL, 0.17 mmol). Acetyl chloride (10 μL, 0.14 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was partitioned between EtOAc and H₂O. The organic layer was dried and concentrated. Purification by silica gel chromatography (EtOAc) yielded N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]ethyl}acetamide (33 mg, 97%) as a white solid.

Example 1BD Preparation of 1-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]ethyl}-3-ethyl-urea (Compound 279)

2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example 1BB, was combined with ethyl isocyanate (18 μL, 0.21 mmol) and pyridine (300 μL). This mixture was stirred at room temperature for 90 minutes, and was then partitioned between EtOAc and aqueous HCl. The organic layer was dried and concentrated. Purification by silica gel chromatography (EtOAc) yielded 1-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-ethyl}-3-ethyl-urea (34 mg, 93%) as a white solid.

Example 1BE Preparation of N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]ethyl}formamide (compound 280)

Acetic anhydride (700 μL) and 98% formic acid (280 μL) were heated at 65° C. for 1 h. This was cooled to 0° C. 2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example 1BB, was taken up in THF (400 μL), and added to the mixed anhydride. This was stirred at 0° C. for 45 minutes. The mixture was then portioned between EtOAc and aqueous NaHCO₃. The organic layer was dried and concentrated. Purification by silica gel chromatography (4/1, CH₂Cl₂/acetone) yielded N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]-ethyl}formamide (28 mg, 86%) as a white solid.

Example 1BF Preparation of 1-ethyl-2-{4-[2-(3-hydroxypyrrolidin-1-yl)-2-oxo-ethoxy]phenyl}-6-methoxy-1H-indole-3-carbonitrile (compound 285)

Step A: 1-Ethyl-2-(4-hydroxyphenyl)-6-methoxy-1H-indole-3-carbonitrile (559 mg, 1.91 mmol), was used to prepare [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid tert-butyl ester (780 mg, 100%) utilizing essentially the same procedure as example 1AZ.

Step B: [4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid tert-butyl ester (745 mg, 1.83 mmol) was stirred in 20% TFA in CH₂Cl₂ at room temperature for 3 hours. This was concentrated and the residue was partitioned between H₂O and EtOAc. The organic layer was dried and concentrated. The residue was triturated with CH₂Cl₂ to yield [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid (634 mg, 99%) as a white solid.

Step C: [4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid (40 mg, 0.12 mmol) was suspended in CH₂Cl₂ (1.65 mmol) and DMF (2 μL). Oxalyl chloride (17 μL, 0.19 mmol) was added. This was stirred at room temperature for 30 minutes. The resulting solution was then pipetted into a stirring solution of S-3-hydroxypyrrolidine (150 μL) and CH₂Cl₂ (3.0 mL). The mixture was washed with aqueous HCl. The organic layer was dried and concentrated. Purification by silica gel chromatography (3/2 CH₂Cl₂/acetone) yielded 1-ethyl-2-{4-[2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-phenyl}-6-methoxy-1H-indole-3-carbonitrile (40 mg, 79%), compound 285 as a white solid.

Example 1BG Preparation of 1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-1H-indole-3-carbonitrile (Compound 332)

Step A: 1-Ethyl-2-(4-hydroxy-3-nitrophenyl)-6-methoxy-1H-indole-3-carbonitrile (369 mg, 1.1 mmol), prepared as in example 1Gd, was combined with EtOAc (20 mL) and Pd/C (150 mg, 10%). This mixture was hydrogenated at 30 p.s.i. for 1 h. This was filtered through celite. The filtrate was concentrated and triturated with ether to yield 2-(3-amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (307 mg, 91%), compound 322, as a white solid.

Step B: 2-(3-Amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.33 mmol), prepared as in step A, was combined with CDI (83 mg, 0.51 mmol), and THF (1.1 mL). This was heated at 65° C. for 1 hour. The reaction mixture was partitioned between EtOAc and aqueous HCl. The organic layer was dried and concentrated. Purification by silica gel chromatography (9/1, CH₂Cl₂/EtOAc) yielded 1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-1H-indole-3-carbonitrile (89 mg, 81%) as a white solid.

Example 1BH Preparation of 1-ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (compound 334)

Step A: Bromoacetic acid (52 mg, 0.37 mmol) was combined with EDCI hydrochloride (62 mg, 0.4 mmol) and acetonitrile (900 μL) to form a homogeneous solution. 2-(3-Amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.33 mmol), prepared as in example 1BG, step B, was added to the solution. A thick paste soon formed. Another 1.1 mL of acetonitrile was added and the mixture was then stirred at room temperature for 2 hours. The reaction mixture was then partitioned between H₂O and EtOAc. The organic layer was dried and concentrated. Purification by silica gel chromatography (4/1, CH₂Cl₂/EtOAc) yielded 2-chloro-N-[5-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-hydroxyphenyl]acetamide (82 mg, 60%), compound 333, as a white solid.

Step B: 2-Chloro-N-[5-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-hydroxy-phenyl]acetamide (57 mg, 0.13 mmol), prepared in step A, was combined with K₂CO₃ (55 mg, 0.4 mmol), and DMF (400 μL). This was heated at 80° C. for 1 hour. The reaction mixture was then partitioned between H₂O and EtOAc. The organic layer was dried and concentrated. Purification by silica gel chromatography (9/1, CH₂Cl₂/EtOAc) yielded 1-ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (45 mg, 90%) as a white solid.

Example 1BI Preparation of 1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-1H-indole-3-carbonitrile (Compound 340)

Step A: 4-Aminosalicylic acid (4.0 g, 26 mmol) was suspended in H₂SO₄ (26 mL, 2.7M) at −5° C. Sodium nitrite (1.8 g, 26.1 mmol) in H₂O (6.5 mL) was cooled to ice bath temperature and was added dropwise to the aminosalicylic acid mixture over 5 minutes. The resulting suspension was stirred at −5° C. for 15 minutes. A solution of KI (6.8 g, 41 mmol) in H₂SO₄ (13 mL, 1M) was added dropwise to the diazonium salt, with considerable evolution of N₂. The reaction mixture was heated at 70° C. for 20 minutes. The reaction mixture was then partitioned between H₂O and EtOAc. The organic layer was dried and concentrated. Purification by silica gel chromatography (7/3, hexanes/acetone, 1% acetic acid) yielded 4-iodosalicylic acid (5.33 g, 85-90% pure).

Step B: Crude 4-Iodosalicylic acid (1.0 g, 3.8 mmol) was dissolved in THF (28 mL) and Et₃N (1.15 mL, 8.2 mmol). DPPA (1.7 mL, 7.8 mmol) was added. This was heated at 70° C. overnight. The reaction mixture was then partitioned between H₂O and EtOAc. The organic layer was dried and concentrated. Purification by silica gel chromatography (9/1, CH₂Cl₂/EtOAc) yielded 472 mg crude intermediate. Trituration with ether yielded 6-iodo-3H-benzooxazol-2-one (369 mg, 37%) as a white solid.

Step C: 6-Iodo-3H-benzooxazol-2-one (118 mg, 0.45 mmol) was used to prepare 1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-1H-indole-3-carbonitrile, compound 340 (75 mg, 55%), utilizing essentially the same procedure as in example 1Gd.

Example 1BJ Preparation of 1-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (compound 339)

1-Ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (20 mg, 0.058 mmol), prepared as in example 1BH, was combined with NaH (14 mg, 60% suspension in oil, 0.35 mmol). THF (300 μL) was added. This was stirred at room temperature for 5 minutes. A solution of methyl iodide (4.4 μL) in THF (100 μL) was added. This was stirred at room temperature for 1 hour. The reaction mixture was partitioned between EtOAc and aqueous HCl. The organic layer was dried and concentrated. Purification by silica gel chromatography (9/1, CH₂Cl₂/EtOAc) yielded 1-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (16 mg, 76%) as a white solid.

The following compound was prepared similarly: Compound 341.

Example 1BK Preparation of 1-ethyl-2-iodo-6-methoxy-5-nitro-1H-indole-3-carbonitrile (compound 499)

1-Ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.15 mmol), prepared as in example 1Ga, Step A, was suspended in acetic acid (620 μL) at 0° C. Nitric acid (4.25M in AcOH) was added. This was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between CH₂Cl₂ and H₂O. The organic layer was washed with aqueous NaHCO₃, and then was dried and concentrated. Purification by silica gel chromatography (6/4, CH₂Cl₂/hexanes), followed by ether trituration, yielded 1-ethyl-2-iodo-6-methoxy-5-nitro-1H-indole-3-carbonitrile (16 mg, 29%) as a yellow solid.

Example 1BL Preparation of 1′-ethanesulfonyl-1-ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6]biindolyl-3-carbonitrile (compound 753)

Step A: 6-Nitroindoline (3.0 g, 18.3 mmol) was dissolved in THF (45 mL) and Et₃N (3.4 mL, 24.4 mmol) at 0° C. Acetyl chloride (1.5 mL, 21 mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between EtOAc and aqueous HCl. The organic layer was dried and concentrated to yield 1-acetyl-6-nitroindoline (3.8 g, 100%) as a yellow solid.

Step B: 1-Acetyl-6-nitroindoline (3.8 g, 18.3 mmol) was suspended in EtOAc (200 mL). Pd/C (650 mg, 10%) was added, and the mixture was hydrogenated at 40-55 p.si.i. for 2 hours. The mixture was then filtered through celite. The filtrate was concentrated, and the residue was triturated with ether to yield 1-acetyl-6-aminoindoline (3.18 g, 99%) as an orange solid.

Step C: 1-Acetyl-6-aminoindoline (1.5 g, 8.5 mmol) was used to prepare 1-acetyl-6-iodoindoline (1.06 g, 43%), utilizing essentially the same procedure in example 1BI, Step A.

Step D: 1-Acetyl-6-iodoindoline (1.06 g, 3.7 mmol), NaOH (1.16 g, 29 mmol), EtOH (8 mL), and H₂O (6 mL) were heated at 90° C. overnight. The reaction mixture was then partitioned between H₂O and EtOAc. The organic layer was extracted into aqueous HCl. The aqueous layer was in turn basified with NaOH, and was extracted with EtOAc. The organic layer was dried and concentrated. Hexane trituration yielded 6-iodoindoline (577 mg, 64%) as a brown solid.

Step E: 1-Iodoindoline (600 mg, 2.45 mmol) was used to prepare 1-ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6′]biindolyl-3-carbonitrile (535 mg, 67%), utilizing essentially the same procedure as in example 1Gd, Step B.

Step F: 1-Ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6′]biindolyl-3-carbonitrile (30 mg, 0.095 mmol) was used to prepare 1′-Ethanesulfonyl-1-Ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6]biindolyl-3-carbonitrile (24 mg, 62%), utilizing the procedure in example 1Y.

The following compounds were prepared similarly as above: Compounds 752 and 754.

Example 1BM Preparation of 5-acetyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (compound 844)

1-Ethyl-6-methoxy-2-(4-nitrophenyl)-1H-indole-3-carbonitrile (100 mg, 0.3 mmol), prepared by the method of example 1Gc was suspended in 1,2-dichloroethane (500 μL) at 0° C. Acetyl chloride (50 μL, 0.69 mmol) was added, followed by AlCl₃ (55 mg, 0.4 mmol) in one portion. This was stirred at 0° C. for 1 hour, at room temperature for 4 hours, and at 45° C. overnight. The reaction mixture was then partitioned between CH₂Cl₂ and H₂O. The organic layer was dried and concentrated. Purification by silica gel chromatography (195:5 CH₂Cl₂/EtOAc) yielded 5-acetyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (33 mg, 29%) as an orange solid.

Example 1BN Preparation of 1-ethyl-6-methoxy-5-morpholin-4-ylmethyl-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (compound 845)

Step A: 1-Ethyl-6-methoxy-2-(4-nitrophenyl)-1H-indole-3-carbonitrile (100 mg, 0.3 mmol), prepared by the method of example 1Gc, was combined with 1,3,5-trioxane (64 mg, 0.71 mmol) and acetic acid (2.0 mL). 33% HBr in acetic acid (2.0 mL) was added. This was stirred at room temperature for 4 hours. The reaction mixture was then partitioned between CH₂Cl₂ and H₂O. The organic layer was washed with aqueous NaHCO₃, and was subsequently dried and concentrated. The crude material was carried through to the next step.

Step B: Crude 6-bromomethyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (0.3 mmol) was heated with morpholine (150 μl, 1.75 mmol) and DCE (1.0 mL) at 90° C. overnight. The reaction mixture was then partitioned between H₂O and EtOAc. The organic layer was dried and concentrated. Purification by silica gel chromatography (50-100%, EtOAc/CH₂Cl₂), followed by trituration with 1/1 hexane/acetone yielded 1-ethyl-6-methoxy-5-morpholin-4-ylmethyl-2-(4-nitrophenyl)-1H-indole-3-carbonitrile (57 mg, 44% overall yield) as a yellow solid.

Example 1BO 2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-1-cyclopropylmethyl-6-methoxy-1H-indole-3-carbonitrile (compound 716)

Step A: To a solution of 6-methoxyindole (5.88 g, 40.0 mmol) and di-tert-butyl dicarbonate (9.59 g, 44.0 mmol) in DCM (50 mL) was added, at 40° C. while stirring, DMAP (0.10 g). After stirring overnight, the mixture was washed sequentially with 0.1 N HCl, water and brine and dried over anhydrous Na₂SO₄. The solvent was evaporated and the residue was chromatographed (silica gel, EtOAc/hexanes, 1/7) to provide tert-butyl 6-methoxy-1H-indole-1-carboxylate (8.48 g, 86%).

Step B: The above Boc-indole (3.08 g, 12.5 mmol) and isopropylborate (4.83 mL, 21.9 mmol) were dissolved in anhydrous THF (20 mL) and the solution was cooled at 0° C. While stirring, LDA (12.5 mL, 1.5 M mono-THF complex in cyclohexane, 18.7 mmol) was added dropwise. The mixture was stirred at 0° C. for 15 min and then room temperature for 0.5 hr, followed by the addition of HCl (6 N, 3.0 mL, 18 mmol) in a ice-water bath. The organic solvent was removed in vacuo and the residue was suspended in H₂O (100 mL) and acidified with HCl (6 N) to pH 4-5. The precipitate was collected via filtration and washed with water and hexanes and dried in air to provide 1-Boc-6-mehoxyindole-2-boronic acid (3.38 g, 93%).

Step C: To a solution of 4-iodoanilline (3.18 g, 14.5 mmol) in pyridine (15 mL) at 0° C., was added 3-chloropropanesulfonyl chloride (2.3 mL, 18.9 mmol). After the addition, the mixture was stirred for 2 hr at room temperature, and poured into ice-water (200 mL). The organic was separated and the aqueous layer was extracted with DCM (2×50 mL). The combined organics were washed with HCl (2 N, 2×15 mL), water (2×50 mL) and brine (20 mL) consecutively and dried over anhydrous Na₂SO₄. The solvent was then evaporated and the residue was chromatographed to furnish 3-chloro-N-(4-iodophenyl)propane-1-sulfonamide (4.68 g, 90%). The chlorosulfonamide obtained (3.47 g, 9.6 mmol) was then treated with K₂CO₃ (3.33 g, 24.1 mmol) in DMF (50 mL) at 50° C. for 2 hr. The mixture was poured into ice-water (300 mL) and the precipitate was collected and dried in air to provide essentially pure 2-(4-iodophenyl)isothiazolidine-1,1-dioxide (3.11 g, 100%).

Step D: To a mixture of 1-Boc-6-mehoxyindole-2-boronic acid prepared in step B above (0.36 g, 1.25 mmol), 2-(4-iodophenyl)isothiazolidine-1,1-dioxide (0.32 g, 1.0 mmol) and PdCl₂(dppf) (0.037 g, 0.05 mmol) in DMF (4.0 mL), was added aqueous K₂CO₃ solution (1.5 mL, 2.0 M, 3.0 mmol). The mixture was stirred at room temperature overnight and then poured into ice-water (100 mL). The precipitate was collected and washed with water and purified by flash column chromatography (silica gel, DCM/EtOAc, 9/1) to furnish 1-Boc-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-1H-indole (0.43 g, 98%).

The following compound was made similarly: Compound 768

Step D: 1-Boc-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-1H-indole (1.63 g, 3.7 mmol) was treated with TFA (25 mL) in DCM (25 mL) at room temperature for 4 hr. After the removal of the volatiles, the residue was carefully stirred with saturated NaHCO₃ for 0.5 hr. The precipitate was collected via filtration and washed with water thoroughly and dried to provide essentially pure 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole (1.17 g, 92%).

Step E: At 0° C., 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole (0.95 g, 2.8 mmol) was dissolved in DMF (10 mL) and treated with chlorosulfonyl isocyanate (0.36 mL, 4.2 mmol). The mixture was then stirred at room temperature overnight and poured into ice-water (150 mL) then stirred for 0.5 hr. The precipitate was collected via filtration and washed thoroughly with water and dried in air to furnish 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole-3-carbonitrile (0.89 g, 87%).

The following compound was prepared in the same fashion as described above: Compound 829

Step F: To a solution of 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole-3-carbonitrile (73 mg, 0.2 mmol) and K₂CO₃ (69 mg, 0.5 mmol) in DMF (3.0 mL) was added cyclopropylmethyl iodide (0.029 mL, 0.3 mmol). The mixture was stirred at 50° C. overnight and poured into ice-water (10 mL). The precipitate was collected via filtration, washed with water and purified by column chromatography to provide 2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-1-cyclopropylmethylindole-3-carbonitrile, compound 716 (73 mg, 87%).

The following compounds were prepared in the same fashion as described above: Compounds 717, 718, 719, 782, 783, 784.

Example 1BP Preparation of 2-[4-(1,1′-dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-3-oxazol-5-yl-1-propyl-1H-indole (compound 805)

Step A: 2-[4-(1,1′-Dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-indole (900 mg, 2.62 mmol), prepared in example 1BO, step D was used to prepare 2-[4-(1,1′-dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-1-propyl-1H-indole (608 mg, 60%), utilizing essentially the same procedure as example 1A, Step B.

Step B: 2-[4-(1,1′-Dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-1-propyl-1H-indole (50 mg, 0.13 mmol) was used to prepare 2-[4-(1,1′-dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-3-oxazol-5-yl-1-propyl-1H-indole (9 mg, 15% overall yield) according to the protocol in example 1P.

Example BQ Preparation of 2-[4-(cyclopropylsulfonyl)piperazin-1-yl]-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (compound 842)

Step A: To a solution of 1-ethyl-6-trifluoromethylindole-3-carbonitrile (2.54 g, 10.0 mmol), prepared by the method of procedure 1A, in anhydrous THF (20.0 mL), at −78° C. was added LDA (8.3 mL, 1.5 M mono-THF in cyclohexane, 12.5 mmol) dropwise. The mixture was continued for 0.5 hr after the addition, followed by the addition of hexachloroethane and the mixture was then brought to room temperature slowly and stirred for 0.5 hr. The solvent was then evaporated and the residue was treated with water. The organics were extracted with dichloromethane, washed with water and brine and dried over anhydrous Na₂SO₄. The crude product obtained after the removal of the solvent was chromatographed (silica gel, dichloromethane/hexanes, 3/2) to provide 2-chloro-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (1.75 g, 64%).

Step B: The chloroindole obtained above (0.27 g, 1.0 mmol), K₂CO₃ (0.35 g, 2.5 mmol) and N-Boc-piperazine (0.28 g, 1.5 mmol) were stirred at 70° C. in DMF (5.0 mL) for 3 days and then poured into water (50 mL). The precipitate was collected via filtration and washed with water. Chromatography of this crude product (silica gel, dichloromethane/ethyl acetate, 9/1) provided 4-(3-cyano-1-ethyl-6-trifluoromethyl-1H-indol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester, compound 785 (0.30 g, 71%).

The following compound was prepared in the same fashion as described above, by using other amines: Compounds 514, 785, 786.

Step C: 4-(3-cyano-1-ethyl-6-trifluoromethyl-1H-indol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 6.1 mmol) was treated with TFA (5 mL) in dichloromethane (5 mL) for 1 hr at room temperature. After the removal of the volatiles, the residue was treated with saturated NaHCO₃ and the precipitate was collected via filtration, washed with water thoroughly and dried in air to furnish essentially pure 1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (0.20 g, 100%).

Step D: To a solution of 1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (32 mg, 0.1 mmol), pyridine (0.1 mL) in dichloromethaene (1.0 mL) was added cyclopropanesulfonyl chloride (28 mg, 0.2 mmol) and the mixture was stirred at room temperature overnight. This was then diluted with dichloromethane (5 mL), washed with HCl (2 N, 2×2 mL), water (2×5 mL) and brine (5 mL) and chromatographed over silica gel (dichloromethane/ethyl acetate, 9/1) to provide 2-[4-(cyclopropylsulfonyl)piperazin-1-yl]-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile, compound 842 (30 mg, 70%).

The following compounds were prepared in the same fashion as described above, using corresponding sulfonyl chlorides: Compounds 841, 843.

Example 1BR Ethanesulfonic acid [3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-amide (compound 835)

Step A: 6-Bromo-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (0.74 g, 2.0 mmol), compound 831, prepared from 6-bromoindole as described in example 1Gb, was mixed with K₂CO₃ (0.55 g, 4.0 mmol), CuI (0.02 g, 0.1 mmol), tert-butyl carbamate (0.35 g, 3.0 mmol), N,N′-dimethylcyclohexane-1,2-diamine ligand (0.028 g, 0.2 mmol) and anhydrous toluene (5.0 mL) in a sealed tube. The reaction system was flushed with nitrogen and then stirred at 110° C. overnight. After cooling, the solvent was replaced with dichloromethane and chromatographed (silica gel, dichloromethane) to provide [3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-1H-indol-6-yl]-carbamic acid tert-butyl ester (0.68 g, 84%), compound 832.

Step B: Compound 832 prepared in step A above (0.63 g, 1.56 mmol) was treated with TFA/DCM (7.5 mL/7.5 mL) at room temperature for 2 hr, and the volatiles were removed in vacuum. The residue was treated with saturated NaHCO₃ and the precipitate was collected via filtration and washed thoroughly with water, dried in air to provide 6-amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (0.45 g, 96%), compound 833.

Step C: The above amine (31 mg, 0.1 mmol) was treated with ethanesulfonyl chloride (19 mg, 0.15 mmol) in pyridine (1.0 mL) at room temperature overnight to provide, after purification using column chromatography, ethanesulfonic acid [3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-1H-indol-6-yl]-amide (83%), compound 835.

The following compound was prepared in the same fashion as described above: Compounds 830, 834, 836 and 837.

Example 1BS Preparation of [3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-carbamic acid ethyl ester (compound 838)

6-Amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (31 mg, 0.1 mmol), compound 833, prepared in example 1BR, step B was treated with ethyl chloroformate (16 mg, 0.15 mmol) in pyridine (1.0 mL) at room temperature overnight to furnish, after purification using column chromatography [3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-carbamic acid ethyl ester (30 mg, 79%).

Example 1BT Preparation of 1-[3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-3-ethyl-urea (compound 839)

6-Amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (31 mg, 0.1 mmol) was treated with ethyl isocyanate (14 mg, 0.2 mmol) in dichloromethane (1.0 mL) at 40° C. overnight. The precipitate was collected via filtration, washed with dichloromethane an dried in air to furnish, 1-[3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-1H-indol-6-yl]-3-ethyl-urea (36 mg, 95%).

Example 1BU Preparation of 1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea (compound 442)

To solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.172 mmole) in THF (2 mL) was added 2-chloroethyl isocyanate (22 uL, 0.258 mmole) at room temperature. After stirring overnight at reflux, the reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate. The resulting semi-solid was triturated with hexane and the precipitate collected was collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford (62 mg, 91%) of 1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea.

Utilizing essentially the same procedure, the following compounds were prepared: Compounds 295, 362, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 443, 444, 445, 446, 511, 512, 513, 600, 620, 626, 627, 628, 679, 680, 681, 740, 741, 742, 743, 748, 749, 750, 751, 774, 817, 818, 846, 847, 848.

Example 1BV Preparation of 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carbonitrile (compound 771)

To a solution of 1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea (100 mg, 0.252 mmol) in MeOH (10 mL) was added aqueous 1M KOH (504 uL) and then stirred at 49° C. for 24 h. The solvents were removed under reduced pressure. The residue was diluted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous MgSO₄, filtered and concentrated under reduced pressure. The residue was diluted with ethyl acetate and then triturated with hexane and the precipitate collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carbonitrile (56 mg, 62%).

Using essentially the same procedure, the following compounds were prepared: Compounds 770, 778

Example 1BW Preparation of 1-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-1H-indole-3-carbonitrile (compound 638)

To a solution of [4-(3-cyano-1-ethyl-6-isopropoxy-1H-indol-2-yl)-phenyl]-carbamic acid 2-chloro-ethyl ester (30 mg, 0.07 mmol) in DMF (1 mL) was added aqueous K₂CO₃ (10 mg) and then stirred at 50° C. for 18 h. The reaction mixture was poured into cold water and the precipitate collected by filtration and washed with hexane and dried in vacuo to afford the title compound (21 mg, 81%).

The following compounds were made in similar fashion: Compounds 820, 821, 863, 864.

Example 1BX Preparation of {3-[3-cyano-1-ethyl-6-(3-pyrrolidin-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamic acid ethyl ester (compound 530)

Step A: To a solution of [3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.65 g, 4.37 mmole) in DCM (20 mL) was added 1M BBr₃ in DCM (13.12 mL) over a period of 20 min. The reaction mixture was stirred further 1 h at room temperature and then the solvents were removed under reduced pressure. The residue was dissolved in MeOH and then poured into cold water. The precipitate was collected by filtration and washed with hexane and dried in vacuo to afford [3-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.5 g, 98%).

Step B: To a solution of [3-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.2 g, 2.91 mmol) in DMF (10 mL) was added K₂CO₃ (538 mg, 3.9 mmole) and 3-bromo-1-chloroproane (383 uL, 3.9 mmole) and the reaction was stirred for overnight at 50° C. The reaction mixture was then poured into cold water and the precipitate was collected by filtration and washed with hexane and dried in vacuo to afford 1.1 g, 89% of the desired product.

Step C: To a solution of {3-[3-cyano-1-ethyl-6-(3-pyrrolidin-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamic acid ethyl ester (50 mg, 0.12 mmole) in CH₃CN (2 mL) was added DIEA (31 uL, 0.18 mmol), sodium iodide (20 mg, 0.132 mmol) and pyrrolidine (30 uL, 0.36 mmole). The resulting mixture was stirred at reflux temperature for overnight. The solvent was evaporated and the residue was diluted with ethyl acetate and then triturated with hexane and the precipitate collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford 1-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-1H-indole-3-carbonitrile, compound 638 (46 mg, 85%).

The following compounds were made in similar fashion following steps A-C, above: Compounds 441, 447, 491, 492, 493, 504, 525, 526, 527, 528, 529, 531, 532, 533, 534, 535, 536, 537, 538, 539

Example 1BY Preparation of [3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea (Compound 767)

Step A: The starting material 2-(3-amino-phenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (187 mg, 0.642 mmol) was dissolved in anhydrous acetone (3.0 mL). Benzoyl isothiocyanate (107 mg, 0.656 mmol) was added to the solution at room temperature and the mixture was stirred for 17 h during which time a precipitate had formed. The precipitate was filtered, washed with acetone and dried to give 264 mg of 1-benzoyl-3-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea (90% yield) as a light yellow solid.

Step B: A suspension of 1-benzoyl-3-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea (241 mg, 0.530 mmol) in methyl alcohol (2.0 ml) and water (0.5 mL) was stirred at room temperature as sodium hydroxide (31 mg, 0.78 mmol) was added. The reaction mixture was heated to 50° C. for 17 h. The reaction mixture was concentrated to remove methyl alcohol. Water was added to the mixture and the solid was filtered, washed with water and dried to give 179 mg of [3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea, compound 767 (96% yield) as a white solid.

Example 1BZ Preparation of 1-ethyl-6-methoxy-2-[4-(2-phenylquinazolin-4-ylamino)-phenyl]-1H-indole-3-carbonitrile (Compound 458)

A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg, 0.343 mmol), 4-chloro-2-phenyl-quinazoline (83 mg, 0.34 mmol) and diisopropylethylamine (0.10 mL, 0.57 mmol) in absolute ethanol (3 mL) was heated to reflux overnight. The solution was cooled and evaporated, and the residue taken up in ethyl acetate (50 mL). This was washed with water and saturated brine (50 mL each), then dried over anhydrous sodium sulfate, filtered and evaporated. The resulting solid was triturated with ether, collected by filtration and dried under vacuum to afford 1-ethyl-6-methoxy-2-[4-(2-phenylquinazolin-4-ylamino)-phenyl]-1H-indole-3-carbonitrile (139 mg, 0.280 mmol, 82%).

Example 1CA Preparation of diethyl [4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-phosphoramidate (compound 772)

A solution of 2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (148 mg, 0.484 mmol), diethyl chlorophosphate (0.086 mL, 0.58 mmol) and diisopropylethylamine (0.10 mL, 0.57 mmol) in 1,4-dioxane (5 mL) was stirred at ambient temperature for 12 hours, then heated to 80° C. for an additional 24 hours. The solution was cooled and poured into 50 mL of ethyl acetate. This was washed with water and saturated brine (50 mL each), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material was separated by flash chromatography (eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford diethyl [4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-ye-phenyl]-phosphoramidate (108 mg, 0.245 mmol, 51%) as a white powder after evaporation.

Example 1CB Preparation of 1-ethyl-6-methoxy-2-[4-(5-methyl-1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-indole-3-carbonitrile (compound 726)

Step A: To a solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (202 mg, 0.693 mmol) in pyridine (2.0 mL) was added the N-β-(chloroethylamino)sulfonyl chloride (222 mg, 1.39 mmol). The mixture was stirred at room temperature for 17 h then water (12.0 mL) was added and the mixture was extracted with ethyl acetate (3×2 mL). The extract was washed with 10% aqueous HCl (2×2 mL), water (2×2 mL), dried over MgSO₄, filtered and concentrated on a rotary evaporator. The crude product was purified by flash chromatography (0-5%, ethyl acetate/methylene chloride) to give 217 mg of N-(2-chloro-ethyl)-N′-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenyl]sulfamide, compound 724, as a tan solid (75% yield).

In similar fashion the following compounds were prepared: Compounds 540, 541, 542, 574, 576, 704

Step B: To a solution of N-(2-chloro-ethyl)-N′-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenyl]sulfamide (100 mg, 0.241 mmol) in anhydrous DMF (1.25 mL), was added potassium carbonate (71.0 mg, 0.514 mmol). The mixture was stirred at room temperature for 17 h, then diluted with water (7.5 mL). The reaction mixture was extracted with ethyl acetate (3×2 mL) and the extract was washed with water (2×2 mL), dried over MgSO₄ and concentrated to give 2-[4-(1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, compound 725, as a white solid (84 mg, 88% yield).

In similar fashion the following compound was prepared: Compound: 705

Step C: To a solution of 2-[4-(1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (34 mg, 0.086 mmol) in anhydrous DMF (1.0 mL) was added potassium carbonate (25 mg, 0.18 mmol) and iodomethane (20.4 mg, 0.144 mmol). The mixture was stirred at room temperature for 2 h. and then diluted with water (6.0 mL) to give a precipitate. The precipitate was filtered, washed with water and dried to give 1-ethyl-6-methoxy-2-[4-(5-methyl-1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-indole-3-carbonitrile, compound 726, as a white solid (35 mg, 98% yield).

In similar fashion the following compound was prepared: Compound 727.

Example 2 Screening of Low Molecular Weight Compounds Using a Cell-Based HCV IRES Monocistronic Translation Assay

Chemical libraries are screened using a cell-based monocistronic HCV IRES-regulated translation assay designed to closely mimic natural HCV mRNA translation and then compound analogs are made based on hits in the chemical libraries and screened as well. A DNA construct is prepared, termed pHCVIRESmono, in which HCV IRES sequences (HCV 2b, nucleotides 18-347) are inserted between a promoter and the firefly luciferase (Fluc) reporter gene. A stably transfected HepG 2 (hepatoblastoma) cell line (termed HepGmono-4) or a Huh7 cell line (termed Huhmono 7), or a Hela-cell line (termed Helamono), are established by transfection with the pHCVIRESmono DNA by selecting for resistance to hygromycin.

Example 3 Determination of Selectivity for HCV IRES-Regulated Translation Using the Cell-Based Cap-Dependent Translation Assays

Since translation assays are used to screen HCV IRES inhibitors, the selected hits may specifically act on HCV IRES-driven translation or may modulate general protein synthesis in mammalian cells. The compounds that act on general translation will most likely have significant toxicity. To address this possibility, various cell-based cap-dependent translation assays are established for the further evaluation of all selected compounds. Plasmid DNAs containing 130 nucleotides of vector sequence 5′ to Fluc are constructed. This construct is referred to herein as pLuc. A stable cell line is established in cap-dependent translation assays using 293T cells (a human embryonic kidney cell line). HepGmono-4 and pLuc are treated with compound for 20 hours and activity is determined by quantifying the Fluc signal. A five-fold selectivity between the HCV IRES and cap-dependent translation is considered to be desirable. For example, using these cell-based cap-dependent translation assays, Applicants identified compounds that showed IC₅₀ values that were at least 5-fold greater in the cap-dependent translation assays than in the HCV IRES translation assay. FIG. 1 shows an example of a hit that was selective against HCV IRES-regulated translation over cap-dependent pLuc translation. Importantly, the compound had the same level of activity in an HCV IRES monocistronic 293T cell line as in HepGmono-4 (data not shown). It is thus unlikely that the selectivity of the compounds between HepGmono-4 (HepG 2) and the cap-dependent translations (293T) is due to the different cell types used.

Additionally, western blotting assays are used to further demonstrate that the compounds selectively inhibit HCV IRES-driven translation. Both HepGmono-4 and pLuc cells are treated with the compounds as described above, following treatment with the test compounds for 20 hours, cells are collected and lysed in Laminin buffer containing 0.5% SDS. Proteins are separated on a 10% SDS-PAGE, then transferred onto a nitrocellulose membrane, and blotted using antibodies against Fluc (RDI) and β-actin (Oncogene). For example, some of the compounds of the present invention were tested in this manner and as expected, the compounds that selectively inhibited HCV IRES-driven translation in assays using Fluc signal as an end point showed comparable reductions of the luciferase reporter protein levels in HepGmono-4 cells and were relatively inactive against pLuc in the Western blot (data not shown). Importantly, these compounds did not inhibit the expression of endogenous β-actin, the translation of which is cap-dependent in both cell lines. Consistently, compounds that did not show selectivity in the translation assays inhibited protein accumulation in both the HCV IRES and cap-dependent translation assays (data not shown). As expected, the general protein translation inhibitor puromycin also inhibited both the HCV IRES-driven and cap-dependent protein production (data not shown). Therefore, the Western blot results confirm that the compounds of the present invention selectively inhibit HCV IRES-driven translation.

Testing conditions for these cell lines are optimized and the effects of mRNA level on activity of the compounds are controlled by quantitating Fluc mRNA levels by RT real-time PCR. For example, some of the compounds of the present invention were tested in this manner, and no significant differences in Fluc mRNA levels were observed between the HepGmono-4, or the Helamono cells, or the Huhmono cells, and cap-dependent translation cell lines used (data not shown).

Example 4 Evaluation of the Selectivity for HCV IRES-Driven Translation Using Cellular IRES-Mediated Translation Assays

A number of human mRNAs have been shown to harbor IRES elements (18, 19, 39, 44, 45, 91, 126, 130). Although the primary sequences and secondary structures of the HCV IRES are different from those of cellular IRESs, an important test for selectivity is to determine whether the selected compounds are active against cellular IRESs. The VEGF IRES has poor initiation activity in in vitro assays, but demonstrates substantial activity in cell-based translation assays (18, 45). For example, some of the compounds of the present invention were tested and all of the compounds that had good selectivity with respect to cap-dependent translation exhibited at least 5-fold higher IC₅₀ values against the VEGF IRES than against the HCV IRES (data not shown). These data indicate that the selected compounds have selectivity against viral IRES. In addition to having different structures, the VEGF IRES also have different interactions with non-canonical cellular translation factors. These differences may contribute to the selectivity of the HCV IRES inhibitors that we have identified.

Example 5 Evaluation of Cytotoxicity

Effects on cell proliferation are a critical issue for any drug discovery effort. Therefore, a cell proliferation/cytotoxicity assay is used to eliminate any compounds that affect mammalian cell growth. The effects of the selected hits on cell proliferation are tested in human cell lines 293 T and Huh7 (a human hepatoblastoma cell line). Cells are grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, L-glutamine, penicillin, and streptomycin. Cells in log phase are treated with test compounds for three days, with 250 μM being the highest concentration of test compound used. The effect of the compounds on cell proliferation is assessed by using the CellTiter 96 AQueous One Solution Cell Proliferation Assay (Promega, Madison, Wis.). Compounds that have at least 5-fold higher CC₅₀ values relative to IC₅₀ values in HepGmono-4 are considered to have a sufficient window between activity and cytotoxicity and, hence, are selected for further evaluation. For example, some of the compounds of the present invention were tested in this manner, and importantly, all compounds that had good selectivity with respect to cap-dependent translation also demonstrated a greater than 5-fold ratio of CC₅₀ to IC₅₀ values.

Example 6 Evaluation of the Efficacy of the Compounds in the HCV Replicon System

The lack of reliable and readily accessible cell-culture and small animal models permissive for HCV replication has limited the development of new anti-HCV agents. Self-replicating subgenomic HCV systems, termed HCV replicons, have recently been described and have been widely used to assess the efficacy of anti-HCV inhibitors (8, 70, 104). Interferon (IFN) α and inhibitors of the HCV protease and polymerase have been reported to be active in the HCV replicon system (8, 17, 32, 68, 69, 117).

HCV replicons that include bicistronic and monocistronic systems are identified and assays for testing the HCV IRES inhibitors are established. In the bicistronic replicons, the HCV IRES directs the expression of the selective marker (Neo and/or a Fluc reporter), and the EMCV IRES mediates the expression of viral non-structural proteins. In the monocistronic replicon, the HCV IRES directly mediates viral protein synthesis. The HCV IRES inhibitors are analyzed in the bicistronic replicon by quantitating the Flue reporter signal. Replicon-containing cells are cultured with the compounds of the invention for 2 days. Interferon (IFN) α is used as a positive control. For example, the compounds of the present invention were tested in this manner, and the experiments showed that compounds that selectively inhibited HCV IRES-mediated translation inhibited Fluc expression in the bicistronic replicon.

In the following table (Table 1),

-   -   *=replicon or HCV-PV IC50 >2 uM     -   **=replicon or HCV-PV IC50 between 0.5 uM and 2 uM     -   ***=replicon or HCV-PV IC50 <0.5 uM         Replicon IC50 values are determined by firefly luciferase         signal.         HCV-PV IC50 values are determined by viral RNA reduction.

TABLE 1 Mass Compound Melting Spec HCV-PV Replicon Number Point (° C.) [M + H] IC50 μM IC50s μM NMR Data 1 * 2 311.1 * 3 356.0 * 4 279.2 * 5 64-66 201.3 * 6 201.1 * 7 304-305 251.1 ** ¹H NMR (300 MHz, DMSO- d₆): δ 8.23 (1H, d, J = 2.1 Hz), 8.08 (1H, dd, J = 8.8, 2.1 Hz), 7.74 (1H, d, J = 8.8 Hz), 7.55 (2H, t, J = 2.2 Hz), 6.51 (2H, t, J = 2.2 Hz). 8 277.3 ** 9 61-63 215.2 * 10 69-71 229.2 * 11 78-80 243.2 * 12 94-97 277.2 ** 13 161-164 265.3 * 14 206-207 415.2 * ¹H NMR (300 MHz, CDCl₃): δ 8.09 (1H, dd, J = 8.8, 1.7 Hz), 7.75 (1H, d, J = 1.7 Hz), 7.49 (1H, d, J = 8.8 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 6.93 (2H, d, J = 8.8 Hz), 6.15 (1H, s), 3.93 (3H, s), 3.83 (3H, s). 15 225-226 290.3 * 16 175-177 286.3 * 17 248.1 * 18 237.3 * 19 307.4 * 20 159-160 267.2 * 21 125-125 277.3 * 22 146-149 321.1 ** 23 234-235 334.2 *** 24 123-124 307.1 ** 25 291-293 271.2 * ¹H NMR (300 MHz, DMSO- d₆): δ 10.81 (1H, s), 8.63 (1H, d, J = 1.7 Hz), 8.10 (1H, dd, J = 8.8, 1.7 Hz), 7.76 (1H, d, J = 8.8 Hz), 4.35 (2H, q, J = 7.0 Hz), 2.22 (3H, s), 1.26 (3H, t, J = 7.0 Hz). 26 287-288 335.3 ** ¹H NMR (300 MHz, CDCl₃): δ 10.83 (1H, s), 8.23 (1H, s), 8.00 (1H, d, J = 8.8 Hz), 7.92 (2H, d, J = 7.3 Hz), 7.60 (1H, d, J = 8.5 Hz), 7.53-7.43 (1H, m), 7.41-7.30 (2H, m), 4.12 (2H, q, J = 7.3 Hz), 1.31 (3H, t, J = 7.3 Hz). 27 138-140 236.3 ** 28 68-70 272.2 ** 29 oil 284.3 * 30 114-116 292.2 * ¹H NMR (300 MHz, DMSO- d₆): δ 8.19 (1H, d, J = 2.3 Hz), 7.96 (1H, dd, J = 8.8, 2.3 Hz), 7.69 (1H, d, J = 8.8 Hz), 7.38 (1H, t, J = 7 Hz), 4.32 (2H, q, J = 7.0 Hz), 3.81 (3H, s), 3.61 (2H, pentet, J = 7 Hz), 1.29 (3H, t, J = 6.7 Hz), 1.24 (3H, t, J = 7.0 Hz). 31 189-190 264.1 * ¹H NMR (300 MHz, DMSO- d₆): δ 8.11 (1H, d, J = 2.0 Hz), 7.94 (1H, dd, J = 8.5, 2.0 Hz), 7.65 (1H, d, J = 8.5 Hz), 7.54 (2H, br s), 4.21 (2H, q, J = 7.0 Hz), 3.79 (3H, s), 1.20 (3H, t, J = 7.0 Hz). 32 oil 280.2 * 33 113-117 280.2 * 34 137-141 232.1 * 35 318-319 411.0, * ¹H NMR (300 MHz, DMSO- 413.0 (M − H⁻) d₆): δ 11.29 (1H, s), 8.71 (1H, d, J = 2.0 Hz), 8.13 (1H, dd, J = 8.8, 2.0 Hz), 7.98 (2H, d, J = 8.5 Hz), 7.84 (2H, d, J = 8.5 Hz), 7.83 (1H, d, J = 8.8 Hz), 4.41 (2H, q, J = 7.0 Hz), 1.28 (3H, t, J = 7.0 Hz). 36 273-274 380.1 * ¹H NMR (300 MHz, DMSO- d₆): δ 11.58 (1H, s), 8.87 (1H, s), 8.72 (1H, s), 8.53 (1H, d, J = 7.0 Hz), 8.47 (1H, d, J = 7.0 Hz), 8.14 (1H, d, J = 8.5 Hz), 7.91 (1H, t, J = 8.2 Hz), 7.86 (1H, d, J = 8.8 Hz), 4.45 (2H, q, J = 7.0 Hz), 1.30 (3H, t, J = 7.0 Hz). 37 56-60 246.2 * 38  96-100 310.1 * 39 94-98 310.1 * 40 176-180 269.1 * 41 155-175 267.1 * 42 138-143 296.1 * 43 229.2 * 44 293.2 * 45 130-131 215.5 * 46 376.2 * 47 140-145 376.2 * 48 138-142 296.3 ** 49 89-90 376.3 * 50 91-92 259.3 * 51 95-96 229.4 * 52 243.2 * 53 145-147 363.1 ** 54  99-101 272.3 * 55 183-185 292.2 * 56 223-224 301.2 ** 57 130-133 243.2 * 58 76-79 243.2 * 59 81-85 242.2 * 60 133-136 271.2 * 61 153-158 270.2 * 62 262.0 * 63 188-192 333.4 * 64 108-113 301.3 * 65 130-132 331.3 ** 66 119-122 331.3 * 67 132-136 319.3 ** 68 140-147 315.3 ** 69 163-166 316.3 ** 70 142-141 321.2 * 71 199.4 348.2 * 72 144-149 271.3 * 73 oil 259.2 * 74 179-182 325.3 * 75 118-123 271.3 * 76 118-120 293.3 * 77 117-118 307.3 * 78 110-114 287.2 * 79 257-260 332.4 * 80 292-294 356.5 ** 81 209-211 360.5 *** *** 82 223-228 372.5 *** ** 83 221-223 384.4 *** *** 84 232-237 396.4 *** *** 85 163-165 398.3 *** *** 86 158-160 410.3 *** 87 187-189 396.3 *** *** 88 209-213 398.4 *** ** 89 148-155 308.3 ** 90 80-95 364.4 * 91 160-161 301.2 * 92 155-156 317.2 * 93 172.4-172.6 305.3 * 94 262-265 314.4 ** 95 248-251 344.4 ** 96 243-250 329.4 ** 97 164-167 350.4 * 98 180-185 363.2 * 99 123.4-123.8 307.0 * 100 128-129 277.2 * 101 204-209 426.6 ** 102 136.7-136.9 267.2 * 103 90-93 263.2 * 104 190-194 406.4 ** 105 204-206 442.4 * 106 230-243 494.4 * 107 157-158 327.1 * 108 94-96 249.2 * 251.2 109 54-56 263.2 * 265.2 110 128-130 349.3 ** 111 208.5 374.3 * ¹H NMR (CDCl₃, 400 MHz), δ = 7.75-7.72 (m, 2H), 7.13-7.10 (m, 2H), 6.97-6.88 (m, 3H), 6.11 (s, 2H) 112 173.1-173.5 277.3 ** ¹H NMR (CDCl₃, 400 MHz), δ = 7.67 (t, J = 8.4 Hz, 2H), 7.24 (d, J = 14.8 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.96-6.90 (m, 3H), 6.10 (s, 2H), 2.46 (s, 3H) 113 193-194 374.3 * 114 207-298 390.3 * 115 175-177 177.1 * 116 116-118 349.4 * 117 120-123 249.3 * 118 62-65 205.2 ** 119 126-128 283.2 ** 120 69-71 205.5 * 121 167-169 364.5 ** 122 163-169 426.5 * 123 113-117 239.4 * 124 212.2-212.3 295.3 * CDCl₃, 400 MHz, δ = 7.61 (dd, J = 8.4 Hz and 4.4 Hz, 1H), 7.04-6.96 (m, 2H), 6.77 (m, 3H), 6.12 (s, 2H), 2.42 (s, 3H) 125 151.2-151.7 291.3 ** CDCl₃, 400 MHz, δ = 7.57 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.86 (s, 1H), 6.79 (dd, J = 11.2 Hz and 2.0 Hz, 2H), 6.12 (s, 2H), 2.42 (s, 3H), 2.40 (s, 3H) 126 146-148 251.3 * 127 173-175 327.3 * 128 218-220 334.5 * 129 188-190 370.4 ** 130 227-233 394.5 *** 131 199-204 408.5 ** 132 209-212 422.5 ** 133 144-146 351.5 ** 134 155-157 335.4 ** 135 168-170 369.5 ** 136 159-161 381.4 ** 137 129-132 345.5 ** 138 235-239 358.5 *** ** 139 191-195 388.5 *** ** 140 83-96 253.3 * 141 145-146 253.4 * 142 103-105 237.4 * 143 168-171 384.5 * 144  97-100 315.4 ** 145 110-113 357.5 ** 146 169-172 335.3 ** 147 183-186 344.4 ** 148 155-157 335.4 ** 149 134-136 345.4 ** 150 141-143 319.4 ** 151 146-148 319.4 ** 152 207-211 386.5 * 153 225-228 398.5 * ** 154 293.1 ** DMSO, 400 MHz, δ = 8.13 (d, J = 6.4 Hz, 1H), 8.01 (s, 2H), 7.84 (s, 1H), 7.54 (dd, J = 12.4 Hz and 3.6 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H) 155 ** CDCl₃, 300 MHz, δ = 9.31 (s, 1H), 8.32 (s, 1H), 8.19-8.17 (m, 1H), 7.75 (s, 1H), 2.70 (s, 3H) 156 205-209 421.5 ** 157 149-153 422.5 ** 158 153-156 317.5 ** 159 147-150 361.3 ** 160 117-119 315.7 ** 161 174-176 340.3 ** 162 185-190 413.5 * 163 235-239 410.5 ** 164 273-280 358.5 ** 165 211-225 373.5 * 166 236-240 385.5 *** 167 196-200 464.5 ** 168 199-204 394.5 * 169 147-150 316.5 ** 170 148-151 307.4 ** 171 134-137 307.4 ** 172 221-223 317.4 ** 173 150-153 316.5 ** 174 139-142 302.4 ** 175 132-135 359.5 ** 176 162-164 343.5 ** 177 125-130 331.4 ** 178 119-123 369.4 * 179 79-80 239.4 ** 180 170-171 384.5 ** ** 181 177-178 398.5 ** 182 148-154 408.5 *** 183 276-284 344.5 ** 184 197-200 337.4 ** 185 157-160 355.4 ** 186 166-169 317.4 ** 187 187-191 321.4 ** 188 209-212 287.4 ** 189 252-253 356.4 * 190 234-236 370.4 ** 191 208-210 370.4 ** * 192 205-207 384.5 ** 193 228-232 378.5 [M − H] ** 194 278-284 370.4 ** 195 271-275 398.4 ** 196 187-189 354.3 ** 197 147-149 373.6 * 198 163-165 395.7 * 199  156-158. 369.2 *** * 200 187-189 354.4 ** 201 147-150 381.2 ** 202 137-139 369.4 ** 203 257.9 ** DMSO, 300 MHz, δ = 10.34 (s, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.14 (d, J = 2.1 Hz, 1H), 6.87 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 2.12 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H) 204 320.1 *** DMSO, 300 MHz, δ = 10.81 (s, 1H), 8.02 (t, J = 7.2 Hz, 2H), 7.67-7.47 (m, 4H), 7.21 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 8.4 Hz and 2.1 Hz, 1H), 4.12 (q, J = 6.9 Hz, 2H), 3.83 (s, 3H), 1.24 (t, J = 7.5 Hz, 3H) 205 181-184 358.4 ** 206  187-191. 372.4 ** 207  179-183. 386.4 ** 208  192-194. 394.4 ** 209  180-183. 408.4 ** 210 213-216 422.4 ** 211  186-191. 384.4 ** 212 180-183 400.4 ** 213 165-168 398.4 ** 214 254.8-255.1 338.1 *** ¹H NMR (DMSO, 300 MHz), δ = 7.88 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 9.9 Hz, 1H), 7.64 (q, J = 8.1 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.56-7.48 (m, 2H), 7.21 (d, J = 2.1 Hz, 1H), 6.91 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 4.13 (s, 3H), 1.23 (t, J = 6.9 Hz, 3H) 215 245-246 345.1 ** ¹H NMR (DMSO, 300 MHz), δ = 11.08 (s, 1H), 8.16 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 6.91 (dd, J = 8.4 Hz and 1.8 Hz, 1H), 4.08 (q, J = 2.1 Hz, 2H), 3.80 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H) 216 261   283.9 ** ¹H NMR (DMSO, 300 MHz), δ = 10.58 (br, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 6.86 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 2.04 (br, 1H), 1.21 (t, J = 6.9 Hz, 3H), 0.89-0.84 (m, 5H) 217 272-273 315.9 *** ¹H NMR (DMSO, 300 MHz), δ = 9.94 (s, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 2.1 Hz, 1H), 6.87 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.91 (d, J = 6.6 Hz, 2H), 3.80 (s, 3H), 1.89-1.92 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H), 0.89 (d, J = 6.6 Hz, 6H) 218 174-177 344.3 ** 219 145-149 388.4 ** 220 219-223 387.7 ** 221 195-200 421.3 ** 222 216-219 385.4 ** 223 210-216 316.4 ** 224 245-249 358.3 ** 225 231-236 372.3 ** 226 294-295 375.9 * ¹H NMR (CDCl₃, 300 MHz) δ (ppm), 3.72 (s, 3H), 3.80 (s, 3H), 6.75-6.91 (m, 2H), 7.42-7.56 (m, 2H), 8.04 (d, 1H), 8.23 (d, 1H), 8.67 (d, 1H). 227 198-203 392.3 ** 228 195-198 388.3 * 229 142-147 321.3 * 230 218-220 323.4 * 231 201-203 289.3 * 232 190-193 307.3 * 233 232-234 329.4 ** 234 221-223 288.3 * 235 218-222 316.4 ** 236 145-147 287.3 * 237 146-148 303.3 * 238 189-191 273.3 * 239 212-218 292.3 * 240 164-167 335.3 * 241 184-188 344.3 * 242 242-248 334.3 * 243 194-198 370.3 *** 244 187-190 360.4 ** 245 192-195 390.4 * 246 160-164 374.4 * 247 212-217 293.3 * 248 117-121 351.4 ** 249 132-136 337.4 ** 250 160-162 323.3 * 251 186-187 398.4 *** ** 252 176-177 432.4 ** 253 121-125 399.2 ** 254 153-154  307.21 * 255 149-151 435.5 ** 256 230-232 331.3 * 257 174-176 330.3 * 258 146-148 330.3 * 259 foam 358.3 * 260 109-111 359.3 * 261 138-143 406.4 ** 262 117-121 365.4 ** 263 121-127 419.4 ** 264 glass 406.5 ** 265 204-206 355.3 * 266 96-99 362.4 ** 267 106-112 336.4 * 268 137-143 414.4 ** 269 153-158 428.4 ** 270 175-177 404.4 * 271 158-160 418.4 ** 272 173-176 396.4 ** 273 207-209 404.4 * 274 166-172 378.4 * 275 201-206 384.4 * 276 224-228 426.4 * 277 186-191 370.4 * 278 234-240 356.4 * 279 197-202 407.5 * 280 89-95 364.4 * 281 132-134 283.3 * 282 135-136 317.3 * 283 215-218 353.4 * 284 112-114 267.3 * 285 185-190 420.5 * 286 191-192 333.3 ** ¹H NMR (300 MHz, CDCl₃): δ 7.92-7.88 (2H, m), 7.67 (1H, s), 7.66 (1H, d, J = 8.8 Hz), 7.46-7.42 (2H, m), 6.98 (1H, dd, J = 8.8, 2.3 Hz), 6.88 (1H, d, J = 2.3 Hz), 4.35 (2H, q, J = 7.3 Hz), 3.92 (3H, s), 1.46 (3H, t, J = 7.3 Hz). 287 175-177 384.4 * 288 194-199 293.3 * 289 173-175 432.2 * 290 433.1 * ¹H NMR (CDCl3, 300 MHz), δ7.97-7.92 (m, 2H), 7.70-7.62 (m, 3H), 7.10 (br, 1H), 6.98 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 4.16 (q, J = 7.5 Hz, 2H), 3.91 (s, 3H), 3.77 (t, J = 4.2 Hz, 4H), 3.62 (q, J = 5.4 Hz, 2H), 2.68 (t, J = 5.7 Hz, 2H), 2.59 (br, 4H), 1.36 (t, J = 7.2 Hz, 3H) 291 319.9 * ¹H NMR (CD₃OD, 300 MHz), δ 8.07 (d, J = 7.2 Hz, 2H), 7.79-7.68 (m, 2H), 7.54 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 6.97 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 4.24 (q, J = 7.5 Hz, 2H), 3.90 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H) 292 176-177 348.0 * ¹H NMR (CDCl3, 300 MHz), δ 7.93-7.88 (m, 2H), 7.69-7.60 (m, 3H), 6.98 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.17 (br, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.91 (s, 3H), 3.53 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H) 293 412.5 * 294 364.4 *** 295 609.4 ** 296 392.4 ** 297 378.4 ** 298 394.4 ** 299 376.4 ** 300 392.4 ** 301 412.4 ** 302 382.4 ** 303 374.2 * 304 426.4 ** 305 442.4 * 306 446.4 ** 307 430.4 ** 308 424.3 * 309 490.3 ** 310 378.4 ** 311 392.1 * 312 378.1 * 313 394.1 * 314 376.1 * 315 412.0 * 316 474.1 * 317 382.1 * 318 446.1 * 319 430.1 * 320 426.1 * 321 490.9 * 322 223-230 308.4 * 323 102.9-103.4 447.2 * ¹H NMR (CD₃OD, 300 MHz), δ8.02-8.00 (m, 2H), 7.78-7.68 (m, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.97 (dd, J = 6.6 Hz and 1.5 Hz, 1H), 4.24 (q, J = 7.5 Hz, 2H), 3.90 (s, 3H), 3.68 (t, J = 4.2 Hz, 4H), 3.52 (q, J = 5.4 Hz, 2H), 2.50 (t, J = 6.9 Hz, 6H), 1.86 (br, 2H), 1.28 (t, J = 7.2 Hz, 3H) 324 165.3-165.7 368.1 * (DMSO, 300 MHz), δ 10.56 (s, 1H), 7.85 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.54 (q, J = 7.8 Hz, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.23 (s, 1H), 6.92 (d, J = 8.7 Hz, 1H), 4.27 (s, 2H), 4.18 (q, J = 7.5 Hz, 2H), 3.83 (s, 3H) 1.20 (t, J = 7.2 Hz, 3H) 325 462.1 * (DMSO, 300 MHz), δ 10.30 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.58-7.54 (m, 4H), 7.51-7.49 (m, 2H), 7.04 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 8.7 Hz and 1.8 Hz, 1H), 6.11 (s, 2H), 4.22 (q, J = 7.5 Hz, 2H), 3.83 (s, 3H), 1.21 (t, J = 6.9 Hz, 3H) 326 137-138 396.1 * 327 154-155 386.1 * (DMSO, 300 MHz), δ 10.45 (s, 1H), 8.02 (s, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.55 (q, J = 7.8 Hz, 2H), 7.33 (q, J = 3.6 Hz, 2H), 7.25 (s, 1H), 6.95 (dd, J = 3.6 and J = 2.4 Hz, 1H), 6.70 (q, J = 1.8 Hz, 1H), 4.22 (q, J = 7.5 Hz, 2H), 3.84 (s, 3H), 1.22 (t, J = 6.9 Hz, 3H) 328 174-175 401.1 * (CDCl3, 300 MHz), δ 8.68 (s, 1H), 8.00 (s, 1H), 7.65 (m, 2H), 7.55 (t, J = 8.4 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H), 6.95 (dd, J = 7.2 and 1.8 Hz, 1H), 6.90 (d, J = 2.1, 1H), 6.54 (s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 2.53 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H) 329 175-176 334.0 * (CDCl3, 300 MHz), δ 7.79 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.38 (s, 1H), 7.30 (d, J = 4.5 Hz, 1H), 6.99 (d, J = 2.1 Hz, 1H), 6.92 (d, J = 2.1 Hz, 1H) 4.19 (q, J = 6.9 Hz, 2H), 3.91 (s, 3H), 2.22 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H) 330 237-238 438.1 * (DMSO, 300 MHz), δ 10.90 (s, 1H), 8.71 (s, 1H), 8.18 (d, J = 9.9 Hz, 1H), 8.06 (s, 1H), 7.97 (t, J = 9.3 Hz, 2H), 7.63 (t, J = 8.1 Hz, 1H), 7.53 (d, J = 8.7, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 6.94 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 4.23 (q, J = 6.6 Hz, 2H), 3.84 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H) 331 160-165 370.5 ** 332 239-145 334.5 * 333 237-240 384.5 ** 334 242-246 348.5 ** 335 87-88 297.5 ** 336 129-132 384.5 * 337 135-137 283.4 * 338 125-135 367.5 [M − H] * 339 215-219 362.5 ** 340 243-248 334.2 * 341 227-230 348.3 ** 342 258-261 337.3 * ¹H NMR (300 MHz, CDCl₃): δ 8.70 (1H, s), 7.79 (1H, d, J = 1.8 Hz), 7.73 (1H, dd, J = 8.5, 1.8 Hz), 7.07 (1H, d, J = 8.5 Hz), 6.95 (2H, d, J = 8.8 Hz), 6.65 (2H, d, J = 8.8 Hz), 3.97 (2H, q, J = 7.0 Hz), 3.54 (3H, s), 1.12 (3H, t, J = 7.0 Hz). 343 131-133 373.5 * 344 177-178 356.5 ** 345 191-192 370.5 ** 346 178-180 384.3 *** 347 146-148 357.3 * 348 126-128 267.2 * 349 392.3 *** 350 374.3 ** 351 390.3 ** 352 388.3 ** 353 350.2 *** 354 388.3 ** 355 384.2 * 356 404.3 [M − H] * 357 392.3 * 358 374.3 * 359 390.3 * 360 388.3 * 361 404.3 * 362 609.5 [M − H] ** 363 201-207 394.2 [M − H] ** 364 183-188 398.2 ** 365 oil 408.2 *** 366 223-225 420.2 *** 367 225-227 434.2 ** 368 168-170 434.2 ** 369 174-177 470.2 ** 370 159-164 432.2 * 371 168-170 340.2 * ¹H NMR (300 MHz, DMSO- d₆): δ 10.24 (1H, s), 7.75-7.60 (1H, m), 7.60 (2H, d, J = 8.8 Hz), 7.45-7.25 (3H, m), 7.41 (2H, d, J = 8.8 Hz), 4.21 (2H, q, J = 7.0 Hz), 3.13 (3H, s), 1.22 (3H, t, J = 7.0 Hz). 372 211-212 334.3 ** ¹H NMR (300 MHz, DMSO- d₆): δ 9.98 (1H, s), 7.73-7.62 (2H, m), 7.69 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8.4 Hz), 7.39-7.24 (2H, m), 4.26-4.12 (4H, m), 1.26 (3H, t, J = 7.0 Hz), 1.20 (3H, t, J = 7.3 Hz). 373 222-228 354.2 [M − H] * 374 180-186 396.2 [M − H] * 375 161-166 425.6 [M − H] * 376 278.4 * 377 153-156 403.1 * ¹H NMR (DMSO, 300 MHz), δ7.66-7.51 (m, 5H), 7.25 (d, J = 2.1 Hz, 1H), 6.91 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 4.20 (q, J = 7.5 Hz, 2H), 3.83 (s, 3H), 3.65-3.55 (m, 2H), 2.73-2.68 (m, 4H), 1.71-1.54 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H). 378 376.7 * ¹H NMR (DMSO, 300 MHz), δ 8.84 (t, J = 1.8 Hz, 1H), 8.02 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 7.8 Hz, 2H), 7.49 (d, J = 8.7 Hz, 1H), 7.38 (s, 1H), 7.22 (s, 1H), 7.02 (s, 1H), 6.89 (d, J = 7.2 Hz, 1H), 4.17 (q, J = 6.9 Hz, 2H), 3.80-3.77 (m, 5H), 1.12 (t, J = 7.2 Hz, 3H). 379 228-232 474.2 ** ¹H NMR (DMSO, 300 MHz), δ7.72-7.67 (m, 2H), 7.78-7.68 (m, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.97 (dd, J = 6.6 Hz and 1.5 Hz, 1H), 4.20 (q, J = 7.5 Hz, 2H), 3.83 (s, 3H), 3.06 (t, J = 4.2 Hz, 6H), 2.76-2.69 (m, 6H), 2.50 (s, 6H), 1.96 (br, 2H), 1.18 (t, J = 7.2 Hz, 3H). 380 * ¹H NMR (DMSO, 300 MHz), δ 10.67 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 4.5 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H), 7.27 (s, 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.28-4.26 (m, 2H), 3.84 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H). 381 216-220 410.1 * ¹H NMR (DMSO, 300 MHz), δ 10.34 (s, 1H), 8.10 (d, J = 8.1 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.26 (s, 1H), 7.14 (d, J = 8.1 Hz, 2H), 6.94 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 4.21 (q, J = 6.9 Hz, 2H), 3.83 (s, 3H), 2.25 (s, 3H), 1.17 (t, J = 6.9 Hz, 3H). 382 236-238 ** ¹H NMR (DMSO, 300 MHz), δ 10.55 (s, 1H), 8.10 (d, J = 7.8 Hz, 2H), 7.83-7.76 (m, 4H), 7.54 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.27 (s, 1H), 6.93 (dd, J = 9.9 Hz and 1.2 Hz, 1H), 4.22 (q, J = 6.9 Hz, 2H), 3.84 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H). 383 161.2-162.2 362.1 * ¹H NMR (CDCl3, 300 MHz), δ 7.79 (s, 1H), 7.65-7.59 (m, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.30 (t, J = 11.4 Hz, 2H), 6.96 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.91 (s, 3H), 2.57-2.52 (m, 1H), 1.36 (t, J = 7.2 Hz, 3H) 1.28-1.23 (m, 6H). 384 199-201 348.0 * ¹H NMR (CDCl3, 300 MHz), δ 7.93 (d, J = 8.4 Hz, 2H), 7.67-7.61 (m, 3H), 6.98 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 6.14 (br, 1H), 4.14 (q, J = 7.5 Hz, 2H), 3.93 (s, 3H), 3.57-3.53 (m, 2H), 1.36-1.26 (m, 6H). 385   213-213.9 362.0 ** ¹H NMR (DMSO, 300 MHz), δ 8.37 (d, J = 6.6 Hz, 1H), 7.98 (d, J = 7.8 Hz, 2H), 7.65 (d, J = 7.8 Hz, 2H), 7.50 (d, J = 9.0 Hz, 1H), 7.23 (s, 1H), 6.90 (d, J = 7.8 Hz, 1H), 4.19-4.16 (m, 2H), 4.08-4.06 (m, 1H), 3.80 (s, 3H), 1.14-1.12 (m, 9H). 386 198-199 359.9 * ¹H NMR (DMSO, 300 MHz), δ 8.59 (d, J = 4.2 Hz, 1H), 7.97 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.7 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 2.90-2.80 (m, 1H), 1.16 (t, J = 7.2 Hz, 3H), 0.69 (q, J = 4.8 Hz, 2H), 0.57 (q, J = 3.3 Hz, 2H). 387   189-189.5 360.1 * ¹H NMR (DMSO, 300 MHz), δ 7.81 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.7 Hz, 1H), 7.25 (d, J = 1.8 Hz, 1H), 6.93 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 4.35 (t, J = 6.8 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 4.06 (t, J = 6.8 Hz, 2H), 3.83 (s, 3H), 2.24 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H). 388 160.1-161.8 363.9 * ¹H NMR (DMSO, 300 MHz), δ 8.60 (t, J = 2.1 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 9.0 Hz, 1H), 7.25 (s, 1H), 6.93 (dd, J = 6.9 Hz and 1.8 Hz, 1H), 4.72 (t, J = 5.4 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 3.48 (q, J = 6.0 Hz, 2H), 3.33 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H). 389 130-132 447.1 * ¹H NMR (CDCl3, 300 MHz), δ 8.36 (br, 1H), 8.12 (d, J = 7.2 Hz, 2H), 7.67-7.59 (m, 3H), 6.97 (dd, J = 9.3 Hz and 1.8 Hz, 1H), 6.89 (s, 1H), 4.18 (q, J = 7.5 Hz, 2H), 3.98 (br, 2H), 3.84 (s, 3H), 3.67 (q, J = 6.9 Hz, 2H), 2.87 (br, 4H), 2.17 (s, 1H) 2.14 (br, 1H), 2.09 (s, 1H), 1.40 (t, J = 10.5 Hz, 3H), 1.31 (t, J = 7.5 Hz, 3H). 390   236-236.8 396.1 * ¹H NMR (DMSO, 300 MHz), δ 10.42 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 7.79-7.75 (m, 4H), 7.55 (d, J = 8.7 Hz, 1H), 7.35 (t, J = 10.6 Hz, 2H), 7.27 (d, J = 2.1 Hz, 1H), 7.09 (t, J = 10.6 Hz, 1H), 6.94 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 4.23 (m, 2H), 3.84 (s, 3H), 1.18 (t, J = 6.9 Hz, 3H). 391 240-242 ** ¹H NMR (DMSO, 300 MHz), δ 10.55 (s, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.82 (m, 4H), 7.55 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 9.0 Hz, 2H), 7.27 (d, J = 1.8 Hz, 1H), 6.94 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.78 (t, J = 7.1 Hz, 3H). 392 243-246 456.1 * ¹H NMR (DMSO, 300 MHz), δ 10.27 (s, 1H), 8.11 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 7.29 (s, 1H), 6.96-6.91 (m, 2H), 4.25 (q, J = 8.5 Hz, 2H), 3.84 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H). 393 202-206 296.4 ** 394 192-195 372.3 [M − H] *** 395 397.4 ** 396 377.2 *** *** 397 377.5 *** *** 398 391.5 *** 399 375.5 *** 400 411.3 ** 401 363.3 *** *** 402 439.5 ** 403 453.5 ** 404 425.5 * 405 425.5 ** 406 503.5 *** 407 483.5 ** 408 231-235 358.1 ** 409 163-164 398.3 ** 410 139-141 359.2 ** 411 148-149 373.3 ** 412 143-144 373.3 * 413 184-185 370.4 *** 414 156-157 384.4 ** 415 163-165 384.4 *** 416 173-175 398.4 *** 417 199-201 398.4 *** 418 183-184 412.4 *** 419 213-215 398.4 ** 420 241-243 372.5 ** 421 214-216 406.3 * 422 259-261 386.5 ** 423 291-294 434.4 * 424 150-153 443.5 * 425 273-275 398.4 ** 426 178-180 327.2 ** 427 199-202 330.3 ** 428 144-146 319.2 [M − H] * 429 200-206 314.3 ** 430 180-186 372.4 [M − H] ** 431 167-173 296.4 * 432 160-162 318.1 * (DMSO, 300 MHz), δ 8.64 (t, J = 5.4 Hz, 1H), 8.02 (d, J = 8.1 Hz, 2H), 7.80-7.65 (m, 4H), 7.40-7.28 (m, 2H), 4.21 (q, J = 6.9 Hz, 2H), 3.29 (q, J = 7.2 Hz, 2H), 1.20-1.08 (m, 6H). 433 187-189 329.9 * (DMSO, 300 MHz), δ 8.61 (d, J = 3.6 Hz, 1H), 7.79 (d, J = 8.1 Hz, 2H), 7.76-7.64 (m, 4H), 7.40-7.27 (m, 2H), 4.20 (q, J = 7.2 Hz, 2H), 2.88-2.82 (m, 1H), 1.17 (t, J = 7.2 Hz, 3H), 0.69 (q, J = 7.2 Hz, 2H), 0.56 (q, J = 7.8 Hz, 2H). 434 170-175 368.4 * 435 112-117 382.5 * 436 196-202 280.5 * 437 220-227 342.3 [M − H] * 438 188-194 356.3 [M − H] * 439 181-186 358.4 ** 440 177-181 370.3 [M − H] ** 441 459.5 ** 442 397.5 * 443 411.5 * 444 439.5 * 445 453.5 ** 446 503.5 * 447 426.5 *** 448 301-303 436.5 * ¹H NMR (300 MHz, DMSO- d₆): δ 10.65 (1H, s), 7.94 (1H, s), 7.76 (1H, s), 7.48 (1H, d, J = 8.5 Hz), 7.45 (2H, d, J = 8.5 Hz), 7.33 (2H, d, J = 8.5 Hz), 7.21 (1H, d, J = 2.0 Hz), 6.90 (1H, dd, J = 8.5, 2.0 Hz), 4.13 (2H, q, J = 7.0 Hz), 3.82 (3H, s), 3.66 (3H, s), 1.15 (3H, t, J = 7.0 Hz). 449 242-243 518.5 * ¹H NMR (300 MHz, DMSO- d₆): δ 10.59 (1H, s), 8.49 (1H, d, J = 2.3 Hz), 7.81 (1H, dd, J = 9.1, 2.3 Hz), 7.52-7.44 (3H, m), 7.29 (2H, d, J = 8.5 Hz), 7.21 (1H, d, J = 2.3 Hz), 6.90 (2H, d, J = 8.8 Hz), 4.12 (2H, q, J = 7.0 Hz), 3.82 (3H, s), 3.63-3.55 (8H, m), 1.12 (3H, t, J = 7.0 Hz). 450 217-220 402.5 ** 451 179-182 438.4 * ¹H NMR (300 MHz, DMSO- d₆): δ 10.87 (1H, s), 7.94 (1H, dt, J = 5.0, 1.0 Hz), 7.66 (1H, dt, J = 3.5, 1.2 Hz), 7.55-7.48 (3H, m), 7.33 (2H, d, J = 8.0 Hz), 7.22 (1H, d, J = 1.8 Hz), 7.14 (1H, ddd, J = 5.0, 3.8, 1.0 Hz), 6.90 (1H, dt, J = 8.8, 1.0 Hz), 4.13 (2H, q, J = 7.3 Hz), 3.83 (3H, s), 1.13 (3H, t, J = 7.3 Hz). 452 299-301 483.4 * ¹H NMR (300 MHz, DMSO- d₆): δ 10.62 (1H, s), 9.12 (1H, dd, J = 4.1, 1.7 Hz), 8.53-8.45 (2H, m), 8.29 (1H, d, J = 8.5 Hz), 7.78-7.68 (2H, m), 7.44 (1H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.16 (1H, d, J = 2.0 Hz), 6.87 (1H, dd, J = 8.8, 2.0 Hz), 4.04 (2H, q, J = 7.0 Hz), 3.80 (3H, s), 1.06 (3H, t, J = 7.0 Hz). 453 198-200 416.5 ** 454 180-182 412.4 * ¹H NMR (300 MHz, CDCl₃): δ 7.44-7.11 (4.8H, m), 6.97 (1.2H, d, J = 8.4 Hz), 6.78-6.69 (2H, m), 4.00-3.90 (2H, m), 3.713 (1.2H, s), 3.707 (1.8H, s), 2.93 (1H, v br), 2.12 (1.8H, s), 2.09 (1.2H, s), 1.17 (1.2H, t, J = 7.3 Hz), 1.14 (1.8H, t, J = 7.3 Hz). 455 221-223 414.4 * 456 157-159 357.5 ** 457 156-158 464.5 ** 458 272-273 496.5 * ¹H NMR (300 MHz, DMSO- d₆): δ 10.10 (1H, s), 8.62 (1H, d, J = 8.2 Hz), 8.49-8.45 (2H, m), 8.27 (2H, d, J = 8.8 Hz), 7.90 (2H, d, J = 3.8 Hz), 7.72 (2H, d, J = 8.8 Hz), 7.70-7.62 (1H, m), 7.55-7.49 (4H, m), 7.26 (1H, d, J = 2.0 Hz), 6.94 (1H, dd, J = 8.8, 2.0 Hz), 4.27 (2H, q, J = 7.0 Hz), 3.85 (3H, s), 1.24 (3H, t, J = 7.0 Hz). 459 158-163 368.5 ** 460 oil 368.3 [M − H] ** 461 200-205 432.3 *** 462 135-140 444.2 [M − H] *** 463 178-179 359.5 * 464 164-166 401.5 * 465  99-100 401.5 * 466 164-166 385.5 ** 467 169-170 399.5 ** 468 201-202 398.5 ** *** 469 243-245 384.5 ** 470 178-180 426.5 *** 471 154-156 412.2 *** 472 215-217 410.5 *** 473 189-191 424.5 *** 474 218-222 293.5 * 475 178-181 293.5 *** 476 175-178 340.4 ** 477 194-195 418.4 *** 478 172-175 469.5 *** 479 190-192 467.5 * 480 207-208 485.4 *** 481 209-211 482.5 * 482 128-130 471.5 ** 483 149-150 292.2 * ¹H NMR (300 MHz, CDCl₃): δ 7.32-7.25 (2H, m), 7.19 (1H, d, J = 2.4 Hz), 6.97 (1H, dd, J = 8.9, 2.4 Hz), 6.92-6.80 (3H, m), 4.17 (2H, q, J = 7.3 Hz), 3.89 (3H, s), 3.80 (2H, v br), 1.34 (3H, t, J = 7.3 Hz). 484 156-157 334.2 * ¹H NMR (300 MHz, CDCl₃): δ 8.16 (1H, d, J = 8.5 Hz), 8.00 (1H, d, J = 8.7 Hz), 7.68 (1H, d, J = 8.8 Hz), 7.60-7.50 (2H, m), 7.25 (1H, obscurred), 7.10 (1H, d, J = 8.8 Hz), 5.20 (2H, q, J = 7.3 Hz), 4.02 (3H, s), 1.55 (3H, t, J = 7.3 Hz). 485 128-133 440.2 * 486 116-123 454.2 ** 487 175-179 446.2 ** 488 158-164 460.2 *** 489 418.5 ** 490 404.5 ** 491 445.2 * 492 463.2 ** 493 477.2 *** 494 336.2 * 495 126-128 444.3 ** 496 236-239 ** 497 235-239 * 498 192-194 427.5 ** 499 235-250 *** 500 468.2 * 501 420.2 * 502 406.2 * 503 406.2 * 504 412.2 * 505 164-166 384.2 * ¹H NMR (300 MHz, CDCl₃): δ 7.52 (1H, t, J = 7.9 Hz), 7.47 (1H, t, J = 1.9 Hz), 7.36-7.30 (3H, m), 7.18 (1H, d, J = 2.3 Hz), 7.00 (1H, dd, J = 8.9, 2.3 Hz), 6.91 (1H, br s), 4.18 (2H, q, J = 7.3 Hz), 3.90 (3H, s), 3.25 (2H, q, J = 7.3 Hz), 1.43 (3H, t, J = 7.3 Hz), 1.38 (3H, t, J = 7.3 Hz) 506 156-157 364.2 * ¹H NMR (300 MHz, CDCl₃): δ 7.67 (1H, s), 7.48-7.44 (2H, m), 7.33 (1H, d, J = 9.0 Hz), 7.26-7.23 (1H, m), 7.19 (1H, d, J = 2.3 Hz), 6.98 (1H, dd, J = 9.0, 2.3 Hz), 6.79 (1H, s), 4.24 (2H, q, J = 7.3 Hz), 4.19 (2H, q, J = 7.3 Hz), 1.36 (3H, t, J = 7.3 Hz), 1.32 (3H, t, J = 7.3 Hz). 507 152-153 378.2 * ¹H NMR (300 MHz, CDCl₃): δ 7.66 (1H, s), 7.46 (2H, d, J = 5.0 Hz), 7.33 (1H, d, J = 9.0 Hz), 7.26-7.21 (1H, m), 7.19 (1H, d, J = 2.3 Hz), 6.98 (1H, dd, J = 9.0, 2.3 Hz), 6.72 (1H, s), 5.03 (1H, hp, H = 6.1 Hz), 4.19 (2H, q, J = 7.3 Hz), 3.89 (3H, s), 1.36 (3H, t, J = 7.3 Hz), 1.30 (6H, d, J = 6.1 Hz). 508 glass 378.2 * ¹H NMR (300 MHz, CDCl₃): δ 7.67 (1H, s), 7.48-7.45 (2H, m), 7.33 (1H, d, J = 9.0 Hz), 7.27-7.23 (1H, m), 7.19 (1H, d, J = 2.3 Hz), 6.98 (1H, dd, J = 9.0, 2.3 Hz), 6.77 (1H, s), 4.19 (2H, q, J = 7.0 Hz), 4.14 (2H, t, J = 6.7 Hz), 3.89 (3H, s), 1.72 (2H, m, J = 7.0 Hz), 1.37 (3H, t, J = 7.0 Hz), 0.99 (3H, t, J = 6.5 Hz). 509 92-95 412.1 * ¹H NMR (300 MHz, CDCl₃): δ 7.67 (1H, s), 7.48-7.45 (2H, m), 7.33 (1H, d, J = 8.8 Hz), 7.27-7.24 (1H, m), 7.19 (1H, d, J = 2.3 Hz), 6.99 (1H, dd, J = 8.8, 2.3 Hz), 6.83 (1H, s), 4.35 (2H, t, J = 6.0 Hz), 4.19 (2H, q, J = 7.3 Hz), 3.89 (3H, s), 3.66 (2H, t, J = 6.5 Hz), 2.16 (2H, p, J = 6.1 Hz), 1.37 (3H, t, J = 7.3 Hz). 510 210-211 368.3 ** ¹H NMR (300 MHz, 9:1 CDCl₃- DMSO-d₆): δ 9.64 (1H, s), 7.28-7.17 (3H, m), 7.14 (1H, d, J = 9.0 Hz), 7.04 (1H, d, J = 7.3 Hz), 6.91 (1H, d, J = 2.0 Hz), 6.75 (1H, dd, J = 9.0, 2.0 Hz), 3.95 (2H, q, J = 7.3 Hz), 3.66 (3H, s), 2.81 (3H, s), 1.15 (3H, t, J = 7.3 Hz). 511 146-148 377.3 * ¹H NMR (300 MHz, CDCl₃): δ 7.34-7.27 (2H, m), 7.19 (1H, d, J = 2.3 Hz), 6.97 (1H, dd, J = 8.8, 2.3 Hz), 6.88-6.79 (3H, m), 4.17 (2H, q, J = 7.0 Hz), 3.89 (3H, s), 3.87 (2H, v br), 1.34 (3H, t, J = 7.0 Hz). 512 67-69 407.2 * ¹H NMR (300 MHz, CDCl₃): δ 10.06 (1H, s), 7.86 (1H, s), 7.56-7.47 (2H, m), 7.36-7.30 (3H, m), 7.19 (1H, d, J = 2.0 Hz), 7.00-6.96 (1H, m), 4.62 (1H, br), 4.27 (2H, q, J = 7.0 Hz), 4.18 (2H, q, J = 7.0 Hz), 3.89 (3H, s), 1.37 (3H, t, J = 7.0 Hz), 1.33 (3H, t, J = 7.0 Hz). 513 210-211 479.2 * ¹H NMR (300 MHz, 9:1 CDCl₃- DMSO-d₆): δ 8.44 (2H, d, J = 7.0 Hz), 7.61 (1H, s), 7.45 (1H, s), 7.36-7.13 (3H, m), 7.10 (2H, d, J = 8.8 Hz), 6.93 (1H, d, J = 7.6 Hz), 6.89 (1H, d, J = 7.9 Hz), 6.85 (1H, d, J = 2.3 Hz), 6.69 (1H, dd, J = 8.8, 2.3 Hz), 3.94 (2H, q, J = 7.0 Hz), 3.60 (3H, s), 1.08 (3H, t, J = 7.0 Hz). ¹⁹F NMR (300 MHz, 9:1 CDCl₃-DMSO- d₆): δ −63.02 (3F, s). 514 248-250 268.2 * 515 137-139 381.1 ** 516 155-156 395.3 ** ¹H NMR (300 MHz, CDCl₃): δ 7.57 (1H, d, J = 8.5 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.25 (1H, s), 6.95 (1H, dd, J = 9.1, 1.7 Hz), 6.67 (1H, s), 6.54 (1H, t, J = 74.8 Hz), 6.48 (1H, s), 4.15 (2H, q), 3.23 (2H, q), 1.45 (3H, t, J = 7.5 Hz), 1.32 (3H, t, J = 7.2 Hz). 517 160-161 409.1 * 518 197-199 392.1 ** 519 174-175 406.1 *** 520 175-177 420.0 *** ¹H NMR (300 MHz, CDCl₃): δ 7.73 (1H, d, J = 8.4 Hz), 7.52 (2H, d, J = 8.2 Hz), 7.39 (2H, d, J = 8.2 Hz), 7.25 (1H, s), 7.13 (1H, dd, J = 7.5, 2.4 Hz), 6.96 (1H, s), 6.56 (1H, t, J = 74.1 Hz), 4.16 (2H, q), 3.26 (2H, q), 1.46 (3H, t, J = 7.5 Hz), 1.32 (3H, t, J = 6.9 Hz). 521 184-186 [NH−] *** 418.1 522 187-188 [NH−] *** 432.1 523 190-192 [NH−] *** 418.1 524 186-188 434.2 *** 525 458.2 ** 526 490.3 *** 527 493.3 ** 528 475.3 ** 529 459.2 ** 530 461.3 *** 531 479.5 ** 532 458.2 ** 533 490.3 ** 534 493.3 *** 535 475.3 *** 536 459.2 ** 537 461.3 *** 538 459.2 ** 539 477.3 *** 540 182-183 385.2 ** 541 149-151 399.2 * 542 186-188 413.2 ** 543 197-200 324.2 ** 544 263-265 392.2 *** *** 545 203-205 382.2 ** ** 546 208-210 396.2 *** 547 180-182 410.2 *** 548 171-174 402.1 ** 549 150-153 416.1 *** 550 183-185 430.0 ** 551 187-190 462.3 ** 552 185-188 428.1 *** 553 412.2 * 554 388.2 * 555 408.2 * 556 440.2 * 557 454.3 [M − H] ** 558 87-90 406.2 ** 559 92-94 386.2 * 560 207-210 434.2 * 561 182-185 398.2 * 562 oil 420.1 *** 563 210-212 436.1 ** 564 210-211 377.1 ** ¹H NMR (DMSO, 300 MHz), δ 8.61 (t, J = 2.4 Hz, 1H), 8.35 (br, 2H), 8.04 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 4.20 (q, J = 7.5 Hz, 2H), 3.83 (s, 3H), 3.55 (q, J = 6.0 Hz, 2H), 3.09 (br, 2H), 2.60-2.53 (m, 3H), 1.15 (t, J = 7.2 Hz, 3H). 565 228-229 304.2 * ¹H NMR (DMSO, 300 MHz), δ 10.23 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.38-7.22 (m, 2H), 4.20 (q, J = 7.2 Hz, 2H), 2.07 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H). 566 334.1 * ¹H NMR (CDCl3, 300 MHz), δ 8.42 (s, 1H), 7.80-7.76 (m, 3H), 7.54 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.36-7.26 (m, 2H), 4.20 (q, J = 7.2 Hz, 2H), 4.07 (s, 2H), 3.55 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H). 567 238.2-238.6 344.2 ** ¹H NMR (CDCl3, 300 MHz), δ 7.78-7.73 (m, 2H), 7.60 (d, J = 5.7 Hz, 2H), 7.51 (d, J = 5.7 Hz, 1H), 7.38-7.28 (m, 2H), 4.20 (q, J = 6.8 Hz, 2H), 3.26 (br, 1H), 2.43 (br, 2H), 2.27 (br, 2H), 2.06-1.90 (m, 2H), 1.36 (t, J = 6.9 Hz, 3H). 568 195-200 320.0 * ¹H NMR (CDCl3, 400 MHz), δ 7.99 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 7.6 Hz, 2H), 7.35 (d, J = 9.2 Hz, 1H), 7.20 (s, 1H), 7.01 (d, J = 9.0 Hz, 1H), 6.15 (br, 1H), 5.65 (br, 1H), 4.17 (q, J = 6.8 Hz, 2H), 3.90 (s, 3H), 1.36 (t, J = 7.6 Hz, 3H). 569 348.1 ** ¹H NMR (CDCl3, 400 MHz), δ7.93 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.8 Hz and J = 2.4 Hz, 1H), 6.19 (br, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.56-3.52 (m, 2H), 1.38-1.23 (m, 6H). 570 220-222 362.1 ** ¹H NMR (CDCl3, 300 MHz), δ 7.92 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 9.0 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 9.0 Hz and 2.4 Hz, 1H), 6.02 (d, J = 7.8 Hz, 1H), 4.35 (m, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 1.36-1.26 (m, 9H). 571 360.0 ** ¹H NMR (CDCl3, 400 MHz), δ 7.91 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 9.2 Hz and 2.4 Hz, 1H), 6.34 (s, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 2.97-2.93 (m, 1H), 1.34 (t, J = 7.2 Hz, 3H), 0.66 (q, J = 7.2 Hz, 2H), 0.07 (t, J = 2.1 Hz, 2H). 572 168-171 378.0 ** ¹H NMR (CDCl3, 300 MHz), δ 7.96 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.02 (dd, J = 8.4 Hz and 2.4 Hz, 1H), 6.60 (br, 1H), 4.16 (q, J = 6.6 Hz, 2H), 3.90 (s, 3H), 3.68 (q, J = 4.5 Hz, 2H), 3.59 (t, J = 4.8 Hz, 2H), 3.41 (s, 3H), 1.35 (t, J = 6.9 Hz, 3H). 573 417.2 * ¹H NMR (CDCl3, 400 MHz), δ 7.59 (s, 4H), 7.34 (d, J = 8.8 Hz, 1H), 7.20 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 4.15 (q, J = 6.4 Hz, 2H), 3.90 (s, 3H), 3.90-3.79 (m, 2H), 3.60 (br, 1H), 3.54 (q, J = 5.6 Hz, 1H), 2.78 (br, 1H), 2.69-2.67 (m, 1H), 2.61 (br, 2H), 2.41 (d, J = 18.4 Hz, 3H), 2.04 (br, 1H), 1.92 (br, 1H), 1.34 (t, J = 6.8 Hz, 3H). 574 155-161 427.4 * 575 144-146 345.2 ** 576 141-142 425.4 * 577 171-173 345.4 ** 578 171-173 317.4 ** 579 178-179 368.5 [M − H] ** 580 198-200 370.4 *** 581 378.5 ** 582 392.5 ** 583 410.4 ** 584 426.4 * 585 406.5 ** 586 440.4 ** 587 406.5 ** 588 402.5 * 589 422.5 ** 590 446.5 ** 591 420.5 * 592 416.4 * 593 454.5 * 594 412.4 * 595 420.5 * 596 404.4 ** 597 418.5 * 598 169-170 382.5 * ¹H NMR (300 MHz, CDCl₃): δ 7.64 (1H, d, J = 8.8 Hz), 7.53 (1H, t, J = 7.9 Hz), 7.46 (1H, t, J = 1.9 Hz), 7.34-7.29 (2H, m), 6.97 (1H, dd, J = 8.8, 2.3 Hz), 6.95 (1H, s), 6.86 (1H, d, J = 2.3 Hz), 4.08 (2H, t, J = 7.6 Hz), 3.91 (3H, s), 3.13 (3H, s), 1.75 (2H, hx, J = 6.6 Hz), 0.80 (3H, t, J = 7.3 Hz). 599 163-164 398.4 * ¹H NMR (300 MHz, CDCl₃): δ 7.64 (1H, d, J = 8.8 Hz), 7.51 (1H, dd, J = 8.5, 7.3 Hz), 7.44 (1H, t, J = 1.8 Hz), 7.30 (2H, dd, J = 7.9, 2.0 Hz), 6.97 (1H, dd, J = 8.8, 2.3 Hz), 6.86 (1H, d, J = 2.3 Hz), 6.85 (1H, s), 4.08 (2H, t, J = 7.6 Hz), 3.91 (3H, s), 3.25 (2H, q, J = 7.3 Hz), 1.75 (2H, hx, J = 7.6 Hz), 1.42 (3H, t, J = 7.5 Hz), 0.80 (3H, t, J = 7.4 Hz). 600 144-145 391.5 * ¹H NMR (300 MHz, CDCl₃): δ 7.60 (1H, d, J = 8.8 Hz), 7.57-7.54 (1H, m), 7.35-7.31 (2H, m), 7.13-7.09 (1H, m), 6.94 (1H, dd, J = 8.8, 2.0 Hz), 6.84 (1H, d, J = 2.0 Hz), 4.07 (2H, t, J = 7.4 Hz), 3.89 (3H, s), 3.21 (2H, t, J = 7.0 Hz), 1.68 (2H, hx, J = 7.3 Hz), 1.53 (2H, hx, J = 7.3 Hz), 0.91 (3H, t, J = 7.3 Hz), 0.73 (3H, t, J = 7.4 Hz). 601 195-200 400.4 [M − H] *** 602 179-184 398.4 [M − H] *** 603 422.4 * 604 410.3 * 605 175-180 419.4 * 606 166-170 433.4 *** 607 189-194 449.5 *** 608 223-228 452.9 ** 609 230-234 439.4 ** 610 226-231 424.8 ** 611 126-128 396.4 ** 612 198-200 410.4 ** 613 116-117 [NH−] *** 430.4 614 176-177 [NH−] *** 444.4 615 220-225 440.3 [M − H] * 616 143-149 414.4 [M − H] *** 617 164-167 433.8 [M − H] *** 618 205-211 368.4 *** 619 201-206 382.3 ** 620 215-223 367.4 ** 621 187-188 412.4 ** ¹H NMR (300 MHz, CDCl₃): δ 7.64 (1H, d, J = 8.8 Hz), 7.50 (2H, d, J = 8.5 Hz), 7.36 (2H, d, J = 8.5 Hz), 6.97 (1H, dd, J = 8.8, 2.3 Hz), 6.86 (1H, d, J = 2.3 Hz), 6.79 (1H, s), 4.05 (2H, t, J = 7.6 Hz), 3.91 (3H, s), 3.23-3.17 (2H, m), 1.93 (2H, hx, J = 7.3 Hz), 1.73 (2H, hx, J = 7.6 Hz), 1.09 (3H, t, J = 7.4 Hz), 0.79 (3H, t, J = 7.4 Hz). 622 182-183 412.4 ** ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.5 Hz), 7.38 (2H, d, J = 8.5 Hz), 6.96 (1H, dd, J = 8.8, 2.3 Hz), 6.86 (1H, d, J = 2.3 Hz), 6.83 (1H, s), 4.05 (2H, t, J = 7.6 Hz), 3.90 (3H, s), 3.43 (1H, hp, J = 6.6 Hz), 1.73 (2H, hx, J = 7.6 Hz), 1.46 (6H, d, J = 6.6 Hz), 0.79 (3H, t, J = 7.5 Hz). 623 217-218 460.4 ** ¹H NMR (300 MHz, CDCl₃): δ 7.65 (1H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.5 Hz), 7.40-7.28 (5H, m), 7.25 (2H, d, J = 8.5 Hz), 6.97 (1H, dd, J = 8.8, 2.3 Hz), 6.86 (1H, d, J = 2.3 Hz), 6.55 (1H, s), 4.45 (2H, s), 4.05 (2H, t, J = 7.6 Hz), 3.91 (3H, s), 1.74 (2H, hx, J = 7.3 Hz), 0.80 (3H, t, J = 7.4 Hz). 624 187-188 378.5 ** ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H, d, J = 8.5 Hz), 7.57 (2H, d, J = 8.8 Hz), 7.46 (2H, d, J = 8.8 Hz), 6.95 (1H, dd, J = 8.8, 2.3 Hz), 6.85 (1H, d, J = 2.3 Hz), 6.79 (1H, s), 4.26 (2H, q, J = 7.0 Hz), 4.05 (2H, t, J = 7.5 Hz), 3.90 (3H, s), 1.72 (2H, hx, J = 7.6 Hz), 1.34 (3H, t, J = 7.0 Hz), 0.78 (3H, t, J = 7.4 Hz). 625 152-153 392.4 *** ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H, d, J = 8.5 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.46 (2H, d, J = 8.5 Hz), 6.95 (1H, dd, J = 8.5, 2.3 Hz), 6.85 (1H, d, J = 2.3 Hz), 6.77 (1H, s), 4.17 (2H, t, J = 6.7 Hz), 4.05 (2H, t, J = 7.4 Hz), 3.90 (3H, s), 1.73 (2H, hx, J = 7.3 Hz), 1.00 (3H, t, J = 7.4 Hz), 0.78 (3H, t, J = 7.4 Hz). 626 193-194 377.5 ** ¹H NMR (300 MHz, CDCl₃): δ 7.61 (1H, d, J = 8.5 Hz), 7.52 (2H, d, J = 8.8 Hz), 7.41 (2H, d, J = 8.8 Hz), 7.30 (1H, br), 6.96 (1H, dd, J = 8.8, 2.0 Hz), 6.86 (1H, d, J = 2.0 Hz), 4.05 (2H, t, J = 7.6 Hz), 3.90 (3H, s), 3.32 (2H, q, J = 7.3 Hz), 1.71 (2H, hx, J = 7.3 Hz), 1.19 (3H, t, J = 7.3 Hz), 0.77 (3H, t, J = 7.3 Hz). 627 188-189 391.5 *** ¹H NMR (300 MHz, CDCl₃): δ 7.61 (1H, d, J = 8.5 Hz), 7.52 (2H, d, J = 8.8 Hz), 7.41 (2H, d, J = 8.8 Hz), 7.34 (1H, br), 6.96 (1H, dd, J = 8.5, 2.0 Hz), 6.86 (1H, d, J = 2.0 Hz), 4.05 (2H, t, J = 7.4 Hz), 3.90 (3H, s), 3.24 (2H, t, J = 7.0 Hz), 1.72 (2H, hx, J = 7.6 Hz), 1.57 (2H, hx, J = 7.0 Hz), 0.95 (3H, t, J = 7.3 Hz), 0.77 (3H, t, J = 7.3 Hz). 628 221-226 381.4 ** 629 204-210 436.3 * 630 205-210 416.3 ** 631 177-182 428.5 [M − H] ** 632 176-178 366.4 [M − H] ** 633 159-161 380.5 [M − H] ** 634 163-165 396.3 ** 635 200-201 392.5 [M − H] *** 636 97-98 428.4 [M − H] ** 637 398.4 *** 638 390.5 * 639 159-160 412.5 * ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H, d, J = 8.8 Hz), 7.50 (1H, t, J = 7.9 Hz), 7.44 (1H, t, J = 1.8 Hz), 7.33-7.28 (2H, m), 7.18 (1H, s), 6.96 (1H, dd, J = 8.8, 2.3 Hz), 6.86 (1H, d, J = 2.3 Hz), 4.08 (2H, t, J = 7.6 Hz), 3.90 (3H, s), 3.22-3.16 (2H, m), 1.90 (2H, hx, J = 7.8 Hz), 1.74 (2H, hx, J = 7.6 Hz), 1.05 (3H, t, J = 7.4 Hz), 0.79 (3H, t, J = 7.5 Hz). 640 197-198 396.5 ** ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz), 6.95 (1H, dd, J = 8.8, 2.0 Hz), 6.92 (1H, s), 6.85 (1H, d, J = 2.0 Hz), 4.62 (2H, dt, J = 74.3, 4.2 Hz), 4.50 (2H, dt, J = 55.8, 4.2 Hz), 4.05 (2H, t, J = 7.6 Hz), 3.90 (3H, s), 1.72 (2H, hx, J = 7.6 Hz), 0.78 (3H, t, J = 7.4 Hz). ¹⁹F NMR (300 MHz, CDCl₃): δ 5.11 (1F, m). 641 177-178 392.5 ** ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.46 (2H, d, J = 8.5 Hz), 6.95 (1H, dd, J = 8.5, 2.0 Hz), 6.85 (1H, d, J = 2.0 Hz), 6.72 (1H, s), 5.05 (1H, hp, J = 7.1 Hz), 4.05 (2H, t, J = 7.6 Hz), 3.90 (3H, s), 1.72 (2H, hx, J = 7.6 Hz), 1.33 (6H, d, J = 7.1 Hz), 0.78 (3H, t, J = 7.4 Hz). 642 152-153 426.5 ** ¹H NMR (300 MHz, CDCl₃): δ 7.66-7.57 (3H, m), 7.53 (2H, d, J = 8.8 Hz), 6.97 (1H, dd, J = 8.8, 2.0 Hz), 6.86 (1H, d, J = 2.0 Hz), 4.07 (2H, t, J = 7.4 Hz), 3.91 (3H, s), 3.46 (3H, s), 3.40 (1H, hp, J = 7.0 Hz), 1.74 (2H, hx, J = 7.3 Hz), 1.40 (6H, d, J = 7.0 Hz), 0.79 (3H, t, J = 7.4 Hz). 643 150-151 412.4 ** ¹H NMR (300 MHz, CDCl₃): δ 7.64 (1H, d, J = 8.8 Hz), 7.58 (2H, d, J = 9.0 Hz), 7.53 (2H, d, J = 9.0 Hz), 6.97 (1H, dd, J = 8.8, 2.0 Hz), 6.86 (1H, d, J = 2.0 Hz), 4.07 (2H, t, J = 7.6 Hz), 3.91 (3H, s), 3.44 (3H, s), 3.12 (2H, q, J = 7.6 Hz), 1.75 (2H, hx, J = 7.6 Hz), 1.41 (3H, t, J = 7.3 Hz), 0.79 (3H, t, J = 7.5 Hz). 644 348.2 * (DMSO, 300 MHz), δ 10.12 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.7 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.03 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.13 (q, J = 6.9 Hz, 2H), 3.77 (s, 3H), 2.31 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 8.7 Hz, 3H), 1.06 (t, J = 7.5 Hz, 3H). 645 242-244 410.2 * (DMSO, 300 MHz), δ 10.33 (s, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 7.8 Hz, 1H), 7.64-7.56 (m, 4H), 7.51 (d, J = 1.8 Hz, 1H), 7.36-7.07 (m, 2H), 7.06 (d, J = 8.1 Hz, 1H), 6.12 (s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H). 646 356.2 ** (DMSO, 300 MHz), δ10.47 (s, 1H), 8.01-7.96 (m, 3H), 7.72 (d, J = 8.4 Hz, 1H), 7.65-7.59 (m, 3H), 7.38-7.29 (m, 3H), 6.71 (dd, J = 3.9 Hz and J = 1.8 Hz, 1H), 4.22 (q, J = 6.9 Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H). 647 430.1 * (DMSO, 300 MHz), δ 10.56 (s, 1H), 8.12 (d, J = 8.4 Hz, 2H), 7.84-7.76 (m, 4H), 7.67 (d, J = 9.0 Hz, 1H), 7.41 (d, J = 9.0 Hz, 2H), 7.11 (d, J = 8.7 Hz, 1H), 6.98 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H). 648 464.0 ** (DMSO, 300 MHz), δ 10.69 (s, 1H), 8.18-8.09 (m, 3H), 7.82-7.72 (m, 3H), 7.70-7.56 (m, 2H), 7.11 (d, J = 2.1 Hz, 1H), 6.96 (dd, J = 8.1 Hz and 2.4 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H). 649 210-212 410.5 ** ¹H NMR (300 MHz, DMSO- d₆): δ 7.60 (2H, d, J = 8.8 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.8 Hz), 7.25 (1H, d, J = 2.1 Hz), 6.91 (1H, dd, J = 8.8, 2.1 Hz), 4.15 (2H, t, J = 7.3 Hz), 3.833 (2H, t, J = 6.4 Hz), 3.831 (3H, s), 3.57 (2H, t, J = 7.3 Hz), 2.45-2.40 (2H, m), 1.54 (2H, hx, J = 7.3 Hz), 0.62 (3H, t, J = 7.3 Hz). 650 165-166 384.5 ** ¹H NMR (300 MHz, CDCl₃): δ 7.64 (1H, d, J = 8.8 Hz), 7.54 (4H, s), 6.96 (1H, dd, J = 8.8, 2.0 Hz), 6.87 (1H, d, J = 2.0 Hz), 4.84 (1H, br t, J = 6.1 Hz), 4.41 (2H, d, J = 6.1 Hz), 4.13 (2H, q, J = 7.3 Hz), 3.90 (3H, s), 2.97 (3H, s), 1.33 (3H, t, J = 7.3 Hz). 651 146-147 384.5 ** ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H, d, J = 8.8 Hz), 7.56-7.45 (4H, m), 6.96 (1H, dd, J = 8.8, 2.0 Hz), 6.87 (1H, d, J = 2.0 Hz), 4.89 (1H, br t, J = 5.9 Hz), 4.42 (2H, d, J = 5.9 Hz), 4.13 (2H, t, J = 7.0 Hz), 3.91 (3H, s), 2.94 (3H, s), 1.34 (3H, t, J = 7.0 Hz). 652 191-194 418.5 *** 653 foam 469.5 * 654 197-201 485.5 * 655 184-187 424.2 * 656 159-161 346.2 * 657 196-198 388.2 * 658 203-205 400.5 * 659 175-177 458.4 ** 660 215-217 394.5 ** 661 156-158 458.5 *** 662 398.4 *** 663 308.3 * 664 424.4 * 665 444.5 * 666 207-209 424.4 *** 667 242-244 424.4 *** 668 171-174 483.0 ** 669 213-215 461.5 *** ¹H NMR (300 MHz, 9:1 CDCl₃- DMSO-d₆): δ 9.73 (1H, s), 8.76 (1H, s), 8.54 (1H, d, J = 5.2 Hz), 8.11 (1H, d, J = 7.9 Hz), 7.58 (1H, dd, J = 7.9, 5.2 Hz), 7.45 (1H, d, J = 9.3 Hz), 7.28 (4H, s), 6.88-6.82 (2H, m), 5.15 (2H, s), 3.97 (2H, q, J = 7.2 Hz), 2.99 (2H, q, J = 7.3 Hz), 1.21 (3H, t, J = 7.3 Hz), 1.15 (3H, t, J = 7.2 Hz). 670 231-233 473.4 *** ¹H NMR (300 MHz, 9:1 CDCl₃- DMSO-d₆): δ 9.59 (1H, s), 8.87 (1H, s), 8.60 (1H, d, J = 5.2 Hz), 8.35 (1H, d, J = 7.6 Hz), 7.80 (1H, dd, J = 7.6, 5.2 Hz), 7.45 (1H, d, J = 8.5 Hz), 7.32-7.23 (4H, m), 6.88 (1H, d, J = 2.0 Hz), 6.83 (1H, dd, J = 8.5, 2.0 Hz), 5.21 (2H, s), 3.97 (2H, q, J = 7.3 Hz), 2.44-2.35 (1H, m), 1.14 (3H, t, J = 7.3 Hz), 1.07-0.99 (2H, m), 0.84-0.78 (2H, m). 671 221-222 461.4 *** ¹H NMR (300 MHz, 9:1 CDCl₃- DMSO-d₆): δ 9.72 (1H, s), 8.56 (1H, d, J = 5.0 Hz), 8.13 (1H, br t, J = 7 Hz), 7.87 (1H, d, J = 7.6 Hz), 7.53-7.50 (1H, m), 7.41 (1H, d, J = 8.5 Hz), 7.25 (4H, s), 7.01 (1H, d, J = 2.0 Hz), 6.86 (1H, dd, J = 8.5, 2.0 Hz), 5.50 (2H, s), 3.98 (2H, q, J = 7.3 Hz), 2.97 (2H, q, J = 7.3 Hz), 1.19 (3H, t, J = 7.3 Hz), 1.11 (3H, t, J = 7.3 Hz). 672 165-166 415.5 *** ¹H NMR (300 MHz, CDCl₃): δ 7.65 (1H, d, J = 8.8 Hz), 7.55 (4H, s), 6.97 (1H, dd, J = 8.8, 2.3 Hz), 6.88 (1H, d, J = 2.3 Hz), 4.41 (2H, s), 4.14 (2H, q, J = 7.3 Hz), 3.91 (3H, s), 2.91 (3H, s), 2.86 (3H, s), 1.35 (3H, t, J = 7.3 Hz). 673 131-132 398.4 * ¹H NMR (300 MHz, CDCl₃): δ 7.65 (1H, d, J = 8.8 Hz), 7.57-7.48 (4H, m), 6.97 (1H, dd, J = 8.8, 2.0 Hz), 6.88 (1H, d, J = 2.0 Hz), 4.42 (2H, s), 4.15 (2H, q, J = 7.3 Hz), 3.91 (3H, s), 2.89 (3H, s), 2.87 (3H, s), 1.37 (3H, t, J = 7.3 Hz). 674 159-160 414.4 * ¹H NMR (300 MHz, 9:1 CDCl₃- DMSO-d₆): δ 9.67 (1H, s), 7.36 (1H, d, J = 8.8 Hz), 7.31 (2H, d, J = 8.8 Hz), 7.23 (2H, d, J = 8.8 Hz), 6.76 (1H, d, J = 2.0 Hz), 6.72 (1H, dd, J = 8.8, 2.0 Hz), 4.05 (2H, t, J = 5.6 Hz), 3.68 (3H, s), 3.44 (2H, t, J = 5.6 Hz), 3.00 (3H, s), 2.95 (2H, q, J = 7.3 Hz), 1.17 (3H, t, J = 7.3 Hz). 675 460.4 ** ¹H NMR (300 MHz, 9:1 CDCl₃- DMSO-d₆): δ 9.83 (1H, s), 7.61-7.27 (5H, m), 6.82-6.78 (2H, m), 4.10 (2H, t, J = 5.6 Hz), 3.74 (3H, s), 3.56-3.47 (4H, m), 3.16 (2H, t, J = 7.3 Hz), 3.06 (3H, s), 2.21-2.01 (2H, m). 676 174-175 394.4 ** ¹H NMR (300 MHz, 9:1 CDCl₃- DMSO-d₆): δ 8.77 (1H, s), 7.51 (2H, d, J = 8.5 Hz), 7.41 (1H, d, J = 8.5 Hz), 7.31 (2H, d, J = 8.5 Hz), 6.80 (1H, d, J = 2.0 Hz), 6.77 (1H, dd, J = 8.5, 2.0 Hz), 4.12-4.04 (4H, m), 3.72 (3H, s), 3.46 (2H, t, J = 5.6 Hz), 3.04 (3H, s), 1.18 (3H, t, J = 7.2 Hz). 677 133-134 408.4 ** ¹H NMR (300 MHz, CDCl₃): δ 7.64-7.51 (5H, m), 6.98-6.94 (2H, m), 6.78 (1H, s), 4.25 (2H, t, J = 5.7 Hz), 4.17 (2H, t, J = 6.7 Hz), 3.90 (3H, s), 3.63 (2H, t, J = 5.7 Hz), 3.22 (3H, s), 1.73 (2H, hx, J = 7.3 Hz), 1.00 (3H, t, J = 7.4 Hz). 678 184-188 318.3 * 679 212-220 389.5 ** 680 163-168 403.3 *** 681 192-197 403.3 ** 682 194-195 460.4 ** 683 157-159 494.2 ** 684 175-176 412.5 * 685 140-141 448.4 ** 686 173-174 424.5 ** 687 124-125 420.4 *** 688 178-179 410.4 ** 689 204-205 409.5 ** 690 192-193 423.9 ** 691 203-205 383.8 ** 692 175-176 397.8 ** 693 163-164 411.8 *** 694 135-136 383.8 ** 695 159-160 397.8 ** 696 194-196 397.8 ** 697 foam 467.0 *** 698 foam 499.5 ** 699 255-258 427.8 *** 701 188-194 395.8 ** 702 147-150 409.8 ** 703 160-165 424.5 ** 704 169-170 433.4 * 705 199-201 397.4 * 706 151-153 396.4 *** 707 159-161 412.5 ** 708 175-177 426.5 ** 709 166-168 424.4 *** 710 oil 458.5 * 711 oil 424.5 * 712 259-261 316.5 * 713 199-202 474.5 ** 714 52-53 281.4 ** 715 174-175 424.1 *** 716 204-205 422.4 *** ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 0.04-0.12 (m, 2H), 0.41-0.50 (m, 2H), 0.98-1.13 (m, 1H), 2.54-2.67 (m, 2H), 3.45 (t, 2H), 3.87 (t, 3H), 3.91 (s, 2H), 3.99 (d, 2H), 6.93-6.99 (m, 2H), 7.36-7.43 (m, 2H), 7.49-7.56 (m, 2H), 7.61-7.66 (m, 1H). 717 205-207 424.5 ** 718 195-196 450.2 ** 719 192-193 410.2 * 720 172-178 410.5 ** 721 158-160 404.6 ** 722 160-162 432.6 ** 723 175-180 418.6 ** 724 168-170 416.4 ** 725 215-216 397.5 ** 726 221-222 411.4 ** 727 217-218 487.5 ** 728 197-199 479.5 *** 729 213-217 493.6 * 730 210-214 495.2 *** 731 173-174 388.5 *** 732 219-221 378.2 ** 733 146-148 354.5 * 734 167-169 412.5 ** 735 123-125 426.5 *** 736 125-126 [NH−] *** 438.5 737 153-155 [NH−] ** 438.5 738 149-151 [NH−] *** 442.4 739 oil 456.5 * 740 203-205 424.9 ** 741 194-196 438.9 *** 742 171-173 [NH−] ** 451.5 743 129-129 465.5 *** 744 92-93 412.5 *** 745 oil 426.5 *** 746 oil 440.5 * 747 136-137 410.5 *** 748 186-188 391.6 *** 749 176-178 405.6 *** 750 173-174 419.6 *** 751 159-162 405.6 ** 752 198-202 396.5 ** 753 157-161 409.9 *** 754 146-150 424.5 ** 755 357.2 *** ¹H NMR (DMSO, 300 MHz), δ11.02 (s, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 7.2 Hz, 1H), 7.66-7.63 (m, 3H), 7.39-7.26 (m, 3H), 4.22 (q, J = 7.5 Hz, 2H), 1.20 (t, J = 6.9 Hz, 3H). 756 388.0 *** ¹H NMR (CDCl3, 300 MHz), δ 8.04 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 7.2 Hz, 1H), 7.42-7.31 (m, 2H), 4.23 (t, J = 7.8 Hz, 2H), 3.01 (s, 3H), 1.38 (t, J = 7.2, 3H). 757 218-225 358.2 *** ¹H NMR (CDCl3, 300 MHz), δ7.79-7.76 (m, 3H), 7.58 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 7.5 Hz, 2H), 7.39-7.32 (m, 2H), 4.23 (q, J = 7.5 Hz, 2H), 2.71 (s, 3H), 2.54 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H). 758 149-153 320.2 *** 759 376.2 *** ¹H NMR (DMSO, 300 MHz) δ 10.14 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.58-7.45 (m, 3H), 7.22 (d, J = 1.5 Hz, 1H), 6.88 (dd, J = 8.7 Hz and 1.8 Hz, 1H), 4.75-4.67 (m, 1H), 4.15 (q, J = 6.9 Hz, 2H), 2.34 (q, J = 7.6 Hz, 2H), 1.27 (d, J = 6.0 Hz, 6H), 1.16-1.07 (m, 6H). 760 402.2 *** (DMSO, 300 MHz) δ9.99 (s, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.51-7.45 (m, 3H), 7.22 (s, 1H), 6.87 (dd, J = 9.0 Hz and 1.8 Hz, 1H), 4.72-4.69 (m, 1H), 4.15 (q, J = 6.6 Hz, 2H), 2.23-1.80 (m, 7H), 1.26 (d, J = 6.0 Hz, 6H), 1.13 (t, J = 7.2 Hz, 3H). 761 169-173 392.1 *** (DMSO, 300 MHz) δ10.06 (s, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.54-7.46 (m, 3H), 7.22 (d, J = 1.5 Hz, 1H), 6.88 (dd, J = 8.4 Hz and 2.1 Hz, 1H), 4.75-4.66 (m, 1H), 4.15 (q, J = 7.2 Hz, 2H), 4.03 (s, 2H), 3.37 (s, 3H), 1.26 (d, J = 6.0 Hz, 6H), 1.16 (t, J = 7.2 Hz, 3H). 762 190-193 452.3 *** (DMSO, 300 MHz) δ10.20 (s, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.52-7.45 (m, 3H), 7.30-7.21 (m, 5H), 7.18-7.14 (m, 1H), 6.88 (dd, J = 8.4 Hz and 2.1 Hz, 1H), 4.73-4.69 (m, 1H), 4.15 (q, J = 6.6 Hz, 2H), 2.91 (t, J-7.5 Hz, 2H), 2.65 (t, J = 7.6 Hz, 2H), 1.27 (d, J = 6.0 Hz, 6H), 1.14 (t, J = 7.2 Hz, 3H). 763 209.2-209.7 424.3 *** (DMSO, 300 MHz) δ10.54 (s, 1H), 8.93-7.96 (m, 4H), 7.62-7.49 (m, 6H), 7.26 (d, J = 1.8 Hz, 1H), 6.91 (dd, J = 8.7 Hz and 2.1 Hz, 1H), 4.76-4.72 (m, 1H), 4.21 (q, J = 7.2 Hz, 2H), 1.30 (d, J = 6.0 Hz, 6H), 1.18 (t, J = 6.9 Hz, 3H). 764 213.5-231.7 442.2 *** (DMSO, 300 MHz) δ10.52 (s, 1H), 8.06-7.96 (m, 4H), 7.58 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 8.7 Hz, 2H), 7.24 (s, 1H), 6.89 (dd, J = 9.0 Hz and 1.5 Hz, 1H), 4.72-4.66 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 1.27 (d, J = 6.0 Hz, 6H), 1.16 (t, J = 6.9 Hz, 3H). 765 288.5-288.9 438.2 ** (DMSO, 300 MHz) δ10.91 (s, 1H), 8.72 (s, 1H), 8.20 (d, J = 9.3 Hz, 1H), 8.03-7.98 (m, 3H), 7.65-7.62 (d, J = 9.0 Hz, 3H), 7.08 (d, J = 2.4 Hz, 1H), 6.96 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 4.20 (q, J = 6.8 Hz, 2H), 3.81 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H). 766 192.8-193.1 440.1 ** (MeOD, 300 MHz) δ 7.98 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 9.3 Hz, 1H), 7.11 (s, 1H), 6.99 (d, J = 6.6 Hz, 1H), 6.60 (s, 1H), 4.24 (q, J = 7.4 Hz, 2H), 3.87 (s, 3H), 2.54 (s, 3H), 1.30 (t, J = 6.9 Hz, 3H). 767 204-205 350.9 *** 768 170-175 429.4 [M − H] * 769 118-123 473.5 * 770 361.5 * 771 361.5 *** 772 211-212 442.4 *** ¹H NMR (300 MHz, CDCl₃): δ 7.62 (1H, d, J = 8.5 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.13 (2H, d, J = 8.5 Hz), 6.95 (1H, dd, J = 8.5, 1.8 Hz), 6.87 (1H, d, J = 1.8 Hz), 5.67 (1H, d, J = 8.8 Hz), 4.28-4.08 (8H, m), 1.47 (3H, t, J = 6.9 Hz), 1.37 (6H, td, J = 7.0, 0.6 Hz), 1.34 (3H, t, J = 7.3 Hz). 773 191-193 434.9 ** ¹H NMR (300 MHz, CDCl₃): δ 7.60 (1H, d, J = 8.8 Hz), 7.52 (2H, d, J = 8.8 Hz), 7.43 (2H, d, J = 8.8 Hz), 6.94 (1H, dd, J = 8.8, 2.2 Hz), 6.86 (1H, d, J = 2.2 Hz), 4.24 (2H, q, J = 7.0 Hz), 4.22-4.06 (6H, m), 1.47 (3H, t, J = 7.0 Hz), 1.34-1.25 (6H, m). 774 205-206 410.9 ** ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H, d, J = 8.8 Hz), 7.53 (2H, d, J = 9.0 Hz), 7.46 (2H, d, J = 9.0 Hz), 6.98 (1H, br s), 6.96 (1H, dd, J = 8.8, 2.0 Hz), 6.88 (1H, d, J = 2.0 Hz), 4.17-4.09 (4H, m), 3.71-3.61 (4H, m), 1.48 (3H, t, J = 7.0 Hz), 1.34 (3H, t, J = 7.1 Hz). 775 482.1 ** ¹H NMR (300 MHz, CDCl₃): δ 7.64 (1H, d, J = 8.5 Hz), 7.52 (2H, d, J = 9.0 Hz), 7.40 (2H, d, J = 9.0 Hz), 6.97 (1H, dd, J = 8.5, 2.2 Hz), 6.90 (1H, d, J = 2.2 Hz), 4.48 (2H, t, J = 4.7 Hz), 4.26 (2H, t, J = 4.7 Hz), 4.05 (2H, t, J = 7.6 Hz), 3.87 (2H, t, J = 6.6 Hz), 3.45 (2H, t, J = 6.9 Hz), 2.61 (2H, p, J = 7.3 Hz), 2.13 (3H, s), 1.72 (2H, hx, J = 7.3 Hz), 0.79 (3H, t, J = 7.4 Hz). 776 257-258 389.5 *** ¹H NMR (300 MHz, DMSO-d₆): δ 11.32 (1H, s), 7.82 (2H, d, J = 8.8 Hz), 7.61 (2H, d, J = 8.8 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.24 (1H, d, J = 1.8 Hz), 6.91 (1H, dd, J = 8.8, 1.8 Hz), 4.52 (2H, s), 4.18 (2H, q, J = 7.0 Hz), 4.11 (2H, q, J = 7.0 Hz), 1.36 (3H, t, J = 7.0 Hz), 1.16 (3H, t, J = 7.0 Hz). 777 124-127 511.6 *** ¹H NMR (300 MHz, CDCl₃): δ 7.58 (1H, d, J = 8.8 Hz), 7.45 (2H, d, J = 8.8 Hz), 7.39 (2H, d, J = 8.8 Hz), 7.33 (1H, br s), 7.31-7.15 (5H, m), 6.94 (1H, dd, J = 8.8, 2.2 Hz), 6.86 (1H, d, J = 2.2 Hz), 4.84 (1H, t, J = 6.0 Hz), 4.11 (2H, q, J = 7.0 Hz), 4.08 (2H, q, J = 7.3 Hz), 3.74 (3H, s), 3.18 (1H, dd, J = 14.0, 5.6 Hz), 3.07 (1H, dd, J = 14.0, 6.4 Hz), 1.47 (3H, t, J = 7.0 Hz), 1.30 (3H, t, J = 7.3 Hz). 778 225-227 375.5 *** ¹H NMR (300 MHz, CDCl₃): δ 7.73 (2H, d, J = 8.8 Hz), 7.62 (1H, d, J = 8.8 Hz), 7.52 (2H, d, J = 8.8 Hz), 6.95 (1H, dd, J = 8.8, 2.0 Hz), 6.88 (1H, d, J = 2.0 Hz), 4.13 (2H, q, J = 7.0 Hz), 4.12 (2H, q, J = 7.0 Hz), 4.04-3.99 (2H, m), 3.67-3.62 (2H, m), 1.47 (3H, t, J = 7.0 Hz), 1.34 (3H, t, J = 7.0 Hz). 779 265-267 389.5 *** ¹H NMR (300 MHz, DMSO-d₆): δ 8.42 (1H, s), 7.72 (2H, d, J = 8.8 Hz), 7.61 (2H, d, J = 8.8 Hz), 7.53 (1H, d, J = 8.5 Hz), 7.26 (1H, d, J = 2.0 Hz), 6.93 (1H, dd, J = 8.5, 2.0 Hz), 4.25-4.08 (6H, m), 1.36 (3H, t, J = 7.0 Hz), 1.19 (3H, t, J = 7.0 Hz). 780 219-220 463.6 ** ¹H NMR (300 MHz, CDCl₃): δ 7.65 (1H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz), 6.97 (1H, dd, J = 8.8, 2.0 Hz), 6.88 (1H, d, J = 2.0 Hz), 4.18-4.08 (5H, m), 3.09 (3H, s), 3.00 (3H, s), 2.94 (3H, s), 1.53 (3H, d), 1.47 (3H, t, J = 7.0 Hz), 1.34 (3H, t, J = 7.0 Hz). 781 207-208 449.8 *** ¹H NMR (300 MHz, CDCl₃): δ 7.64 (2H, d, J = 8.8 Hz), 7.60 (4H, s), 6.97 (1H, d, J = 8.8, 2.0 Hz), 6.88 (1H, d, J = 2.0 Hz), 4.12 (2H, q, J = 7.0 Hz), 4.11 (2H, q, J = 7.0 Hz), 3.36 (3H, s), 3.23 (2H, s), 3.14 (3H, s), 2.88 (3H, s), 1.48 (3H, t, J = 7.0 Hz), 1.33 (3H, t, J = 7.0 Hz). 782 188-190 396.5 ** 783 201-202 410.5 * 784 245-246 410.5 ** 785 151-153 423.5 ** ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 1.38 (t, 3H), 3.30-3.37 (m, 4H), 3.51-3.58 (m, 4H), 4.06-4.18 (q, 2H), 7.45 (d, 1H), 7.54 (s, 1H), 7.66 (d, 1H). 786 202-203 437.5 * 787 261-263 412.2 * 788 112-114 453.9 * 789 154-156 398.2 *** 790 398.2 *** 791 149-152 396.5 *** 792 182-185 350.5 *** 793 154-155 364.5 *** 794 149-151 378.5 *** 795 183-185 378.5 *** 796 124-125 392.6 ** 797 209-212 277.9 ** 798 193.4-193.7 429.2 * (CD₃CN, 400 MHz) δ9.19 (s, 1H), 7.95 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.8 Hz, 1H), 7.10 (s, 1H), 6.92 (dd, J = 8.8 Hz and 0.8 Hz, 1H), 6.56 (s, 1H), 4.74-4.64 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 2.51 (s, 3H), 1.27 (d, J = 6.0 Hz, 6H), 1.27 (t, J = 7.2 Hz, 3H). 799 362.2 *** ¹H NMR (DMSO, 300 MHz), δ 10.14 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.52-7.50 (m, 3H), 7.22 (s, 1H), 6.91 (d, J = 8.7 Hz, 1H), 4.17 (q, J = 7.5 Hz, 2H), 3.82 (s, 3H), 2.24 (t, J = 7.2 Hz, 2H), 1.60 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H). 801 199-219 374.2 *** ¹H NMR (CDCl3, 300 Hz), 7.72 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 2H), 7.22 (s, 1H), 6.91 (dd, J = 6.6 Hz and 2.1 Hz, 1H), 6.87 (d, J = 2.1 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 3.24-3.18 (m, 1H), 2.46-2.25 (m, 4H), 2.06-1.97 (m, 2H), 1.33 (t, J = 8.1 Hz, 3H). 802 196-198 410.2 ** ¹H NMR (DMSO, 300 Hz), δ 10.45 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.54-7.48 (m, 3H), 7.33-7.21 (m, 6H), 6.92 (dd, J = 6.6 Hz and 2.1 Hz, 1H),, 4.17 (q, J = 6.6 Hz, 2H), 3.82 (s, 3H), 3.67 (s, 2H), 1.15 (t, J = 7.2 Hz, 3H). 803 216-217 386.1 * ¹H NMR (DMSO, 300 Hz), δ 10.90 (s, 1H), 8.71 (s, 1H), 8.19 (d, J = 9.3 Hz, 1H), 8.02-7.98 (m, 3H), 7.63 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 6.6 Hz and 2.1 Hz, 1H), 4.20 (q, J = 6.6 Hz, 2H), 3.83 (s, 3H), 1.16 (t, J = 6.6 Hz, 3H). 804 214-216 401.2 * ¹H NMR (DMSO, 300 Hz), δ 10.92 (s, 1H), 8.00 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 6.6 Hz and 2.1 Hz, 1H), 6.69 (s, 1H), 4.19 (q, J = 6.6 Hz, 2H), 3.83 (s, 3H), 2.49 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H). 805 217-222 452.5 * 806 157-159 422.5 ** 807 171-172 396.5 *** 808 195-197 410.5 ** 809 167-168 410.5 ** 810 209-211 422.5 ** 811 166-168 354.5 * 812 206-208 460.4 ** 813 176-177 458.4 *** 814 164-165 [NH−] * 458.5 815 153-154 473.5 * ¹H NMR (300 MHz, CDCl₃): δ 7.65 (1H, d, J = 8.8 Hz), 7.61 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.8 Hz), 6.98 (1H, dd, J = 8.8, 2.3 Hz), 6.89 (1H, d, J = 2.3 Hz), 4.24 (2H, t, J = 5.4 Hz), 4.17 (2H, q, J = 7.3 Hz), 4.02 (2H, q, J = 5.4 Hz), 3.91 (3H, s), 3.00 (3H, s), 2.01 (3H, s), 1.38 (3H, t, J = 7.3 Hz). 816 186-187 445.5 ** ¹H NMR (300 MHz, CDCl₃): δ 7.66 (1H, d, J = 8.5 Hz), 7.60 (2H, d, J = 8.8 Hz), 7.55 (2H, d, J = 8.8 Hz), 6.98 (1H, dd, J = 8.5, 2.0 Hz), 6.89 (1H, d, J = 2.0 Hz), 4.16 (2H, q, J = 7.3 Hz), 3.93 (2H, t, J = 6.0 Hz), 3.91 (3H, s), 3.53 (2H, t, J = 6.0 Hz), 3.38 (3H, s), 3.07 (3H, s), 1.38 (3H, t, J = 7.3 Hz). 817 188-190 439.2 * 818 158-159 437.0 *** 819 438.9 * 820 408.4 ** 821 408.4 * 822 144-145 439.9 ** 823 93-94 456.2 * 824 169-170 428.2 * 825 109-110 444.2 * 826 160-161 432.1 ** 827 189-191 446.1 *** 828 198-200 431.2 ** ¹H NMR (300 MHz, CDCl₃): δ 7.65 (1H, d, J = 8.8 Hz), 7.62 (2H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.8 Hz), 6.98 (1H, dd, J = 8.8, 2.0 Hz), 6.89 (1H, d, J = 2.0 Hz), 4.17 (2H, q, J = 7.2 Hz), 3.93 (2H, t, J = 5.3 Hz), 3.91 (3H, s), 3.77 (2H, t, J = 5.3 Hz), 3.06 (3H, s), 1.38 (3H, t, J = 7.2 Hz). 829 271-275 422.1 ** 830 178-179 420.1 ** 831 140-141 371.0 * 832 206-207 406.3 ** ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 1.34 (t, 3H), 1.47 (t, 3H), 1.55 (s, 9H), 4.04-4.25 (m, 4H), 6.62 (s, 1H), 6.86-6.92 (m, 1H), 7.02-7.08 (m, 2H), 7.43-7.49 (m, 2H), 7.62 (d, 1H), 7.95 (d, 1H). 833 183-185 306.3 ** ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 1.21 (t, 3H), 1.37 (t, 3H), 3.84-4.09 (m, 6H), 6.54-6.71 (m, 2H), 6.85-7.01 (m, 2H), 7.23-7.45 (m, 3H). 834 179-180 384.2 ** 835 178-179 398.2 ** ¹H NMR (CDCl₃, 300 MHz) δ (ppm), 1.32-1.52 (m, 9H), 3.06-3.17 (q, 2H), 4.07-4.24 (m 4H), 6.55 (s, 1H), 6.99-7.10 (m, 3H), 7.42-7.50 (m, 2H), 7.52-7.53 (m, 1H), 7.69 (d, 1H). 836 167-169 412.2 * 837 144-145 410.2 * 838 193-194 378.1 ** ¹H NMR (CDCl₃, 300 MHz) δ (ppm), 1.31-1.39 (m, 6H), 1.48 (t, 3H), 4.07-4.31 (m, 6H), 6.73 (s, 1H), 6.88-6.95 (m, 1H), 7.01-7.08 (m, 2H), 7.42-7.53 (m, 2H), 7.63 (d, 1H), 7.99 (s, 1H). 839 249-250 377.3 * ¹H NMR (CDCl₃, 300 MHz) δ (ppm), 1.13 (t, 3H), 1.32 (t, 3H), 1.43 (t, 3H), 3.20-3.32 (m, 2H), 4.13-4.26 (m, 4H), 5.77 (t, 1H), 7.06-7.18 (m, 3H), 7.48 (d, 1H), 7.52-7.59 (m, 2H), 8.02 (s, 1H), 8.18 (d, 1H). 840 182-183 442.5 * 841 140-141 429.2 * 842 170-171 427.2 * ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 1.04-1.13 (m, 2H), 1.20-1.28 (m, 2H), 1.44 (t, 3H), 2.30-2.43 (m, 1H) 3.44-3.61 (m, 8H), 4.10-4.23 (q, 2H), 7.49 (d, 1H), 7.56 (s, 1H), 7.72 (d, 1H). 843 143-146 463.1 * 844 220-227 378.1 * 845 210-215 435.0 * 846 201-202 391.5 ** 847 166-167 405.5 ** 848 193-194 453.5 ** 849 159-161 364.5 ** 850 179-180 446.4 ** 851 186-187 410.4 ** 852 171-172 426.4 ** 853 159-161 346.2 *** 854 330.2 ** 855 332.1 ** 856 202-202 368.1 * 857 192-192 364.2 ** 858 362.2 *** 859 191-192 374.2 ** 860 242-244 334.1 ** 861 346.2 ** 862 360.1 * 863 362.5 ** 864 362.5 ** 865 187-192 412.9 *

Example 7 Evaluation of the Activity of Compounds Using an HCV-Poliovirus Chimera

In an HCV-poliovirus (HCV-PV) chimera, the PV 5′ UTR is replaced by the HCV 5′ UTR and partial (the first 123 amino acids) core coding sequences (nucleotides 18 to 710 of HCV 1b) as shown in FIG. 1 (140). As a consequence, the expression of poliovirus proteins is under regulation of the HCV IRES. Poliovirus is a picornavirus in which protein translation initiation is mediated by an IRES element located in the 5′ UTR. At the 5′ end of the HCV-PV chimeric genome, there is the cloverleaf-like RNA structure of PV, an essential cis-acting replication signal ending with the genome-linked protein VPg. Replication kinetics of the HCV-PV chimera matches that of the parental poliovirus (Mahoney) and can result in cytopathic effects (CPE) in cell culture. Heptazyme, a ribozyme that targets the HCV IRES, was shown to be active against the chimeric virus in cell culture (76, 77).

To evaluate compounds for activity against the chimeric virus, HeLa cells are seeded and incubated at 37° C. under 5% CO₂ for 24 hours. The cells are then infected with HCV-PV at a multiplicity of infection (MOI) at 0.1 for 30 min and then treated with compound for 1 day (treatment time will be optimized). The activity of compounds is determined by a change in cytopathic effect, plaque assay, and/or viral RNA production (see e.g., Table 1).

Example 8 Evaluation of the Activity of Compounds Against a Wild-Type Poliovirus (WT-PV) and the Poliovirus IRES Translation Assay (WT-PV Mono Luc)

A DNA construct is prepared, termed pPVIRESmono, in which PV IRES sequences are inserted (nucleotide number 1-742) between a promoter and the firefly luciferase (Fluc) reporter gene. A stably transfected 293 T cell line, is established by transfection with the pPVIRESmono DNA by selecting for resistance to hygromycin. As previously described, cells are treated with compounds for 20 hours, and activity is determined by quantifying the Fluc signal. Additionally, to evaluate compounds activity against wild-type poliovirus, Hela cells are seeded and incubated at 37° C. under 5% CO₂ for 24 hours. Cells are then infected with wild-type poliovirus at a MOI at 0.1 for 30 minutes, and then treated with compound for one day. The activity of compounds is determined by changes in cytopathic effect, plaque assay, and RT-PCR using poliovirus IRES primers and probes (see e.g., Table 2).

Furthermore, if compounds are active against the poliovirus and other virus IRESs, then the compounds are useful for treating viral infection by any virus containing an IRES.

TABLE 2 WT-PV WT-PV WT-PV WTPV Compound CPE CPE CPE mono luc No. (100 μM)* (10 μM)* (1 μM)* IC₅₀ (μM) 4 3 2 1 0.8 5 3 2 1 9 9 3 2 2 >100 10 3 2 2 >100 19 3 2 1 15 24 3 2 2 1.5

Example 9 In Vitro Translation Assay

In vitro translation assays can be used to distinguish between the compounds that act on HCV IRES RNA or cellular translation factors. In exemplary assays, the mRNA that will direct translation is a transcribed runoff product from the T7 RNA polymerase promoter of the pHCVIRESmono plasmid DNA generated with Ambion RNA MegaTranscript kit (Ambion, Inc., Austin, Tex.). In vitro translation is performed using HeLa cell lysates using methods known to one of skill in the art. Preliminary results indicate that one or more of the compounds of the present invention has significantly higher activity against HCV IRES regulated translation after preincubating the compound with the HCV IRES RNA transcripts than after preincubating with HeLa cell lysate for 30 min at 37° C. or without preincubation (data not shown). This suggests that this compound may interact with the HCV IRES RNA in the in vitro translation assay. To demonstrate whether the compounds selectively act on the HCV IRES, pLuc is used together with cellular IRES mRNA transcripts as controls for in vitro translation.

All publications and patent applications cited herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Although certain embodiments have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments without departing from the teachings thereof. All such modifications are intended to be encompassed within the claims of the invention.

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1.-41. (canceled)
 42. A compound of Formula (I):

wherein: X is: -cyano; Y is: amino optionally substituted with one or more C₁ to C₆ alkyl substituents; —NHCOR_(e), where R_(e) is: —C₁ to C₆ alkyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; or aryl optionally substituted with: —C₁ to C₆ alkyl, —C₁ to C₆ alkoxy, cyano, nitro, or halogen; —NHCOOR_(x), where R_(x) is C₁ to C₆ alkyl; —CH₂O—R_(f), where R_(f) is aryl; —NR_(g)R_(h), where R_(g) is C₁ to C₆ alkyl or hydrogen and R_(h) is aryl optionally substituted with C₁ to C₆ alkoxy;

where R_(cc) is: naphthalene, 5 or 6 membered heteroaryl,

aryl, optionally substituted with one or more of the following: —C₁ to C₆ alkoxy, hydroxy, halogen, —C₁ to C₆ alkyl, optionally substituted with cyano, amino optionally substituted with one or more C₁ to C₆ alkyl substituents, —NHPO(R_(x))₂, where R_(x) is as defined above, —NR_(ee)CONR_(ff), where R_(ee) is hydrogen or C₁ to C₆ alkyl, optionally substituted with halogen, and R_(ff) is: hydrogen, —C₁ to C₆ haloalkyl, —C₁ to C₆ haloalkoxy, —C₁ to C₆ alkyl, or —COR_(x), where R_(x) is as defined above, —NR_(gg)COR_(hh), where R_(hh) is: hydrogen, —C₁ to C₆ alkyl optionally substituted with: —C₁ to C₆ alkoxy, halogen, or amino optionally substituted with one or more C₁ to C₆ alkyl substituents, amino optionally substituted with one or more C₁ to C₆ alkyl substituents, where alkyl is optionally substituted with halogen, 5 or 6 membered heterocycle, 5 or 6 membered heteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and R_(gg) is: hydrogen, —C₁ to C₆ alkyl, —C₁ to C₆ haloalkyl, —C₁ to C₆ haloalkoxy, or —COR_(x), where R_(x) is as defined above, —C₁ to C₆ haloalkyl, 5 or 6 membered heterocycle optionally substituted with carboxy or oxo, amino optionally substituted with one or more C₁ to C₆ alkyl substituents, —NR_(ii)SO₂R_(x), where R_(x) is as defined above, and R_(ii) is: hydrogen, —C₁ to C₆ alkyl, —C₁ to C₆ haloalkyl, —C₁ to C₆ haloalkoxy, —COR_(x), where R_(x) is as defined above; Z is: hydrogen; —C₁ to C₆ alkyl optionally substituted with: —C₁ to C₆ alkoxy, one or more halogen substituents, or aryl; aryl optionally substituted with C₁ to C₆ alkoxy or one or more C₁ to C₆ alkyl substituents; R is hydrogen, halogen or C₁ to C₆ alkoxy; R₁ is: hydrogen; hydroxy; halogen; —C₁ to C₆ haloalkyl; nitro; 5 or 6 membered heteroaryl; 5 or 6 membered heterocycle; —C₁ to C₆ alkoxy optionally substituted with: one or more halogen substituents, aryl, or 5 or 6 membered heterocycle; aryl optionally substituted with C₁ to C₆ alkoxy; —COR_(x), where R_(x) is as defined above; —C₁ to C₆ alkyl optionally substituted with di-C₁ to C₆ alkyl-amino or 5 or 6 membered heterocycle; or R₁ joins together with R₂ to form:

R₂ is: nitro; hydrogen; halogen; hydroxy; —C₁ to C₆ alkyl, optionally substituted with one or more halogen substituents; amino; —C₁ to C₆ alkoxy optionally substituted with: one or more halogen substituents, —OCOR_(x), where R_(x) is as defined above, di-C₁ to C₆ alkyl-amino optionally substituted with C₁ to C₆ alkoxy, 5 or 6 membered heterocycle optionally substituted with C₁ to C₆ alkyl, 5 or 6 membered heteroaryl, or aryl; —COOR_(x), where R_(x) is as defined above; —C₁ to C₆ haloalkyl; amide optionally substituted with: hydroxy, or aryl; 5 or 6 membered heteroaryl; —OCOR_(x), where R_(x) is as defined above; —NHCOR_(jj), where R_(jj) is: —C₁ to C₆ alkoxy, or amino optionally substituted with one or more C₁ to C₆ alkyl substituents; —OR_(kk), where R_(kk) is 5 to 6 membered heteroaryl; —NHSO₂R_(x), where R_(x) is as defined above; or R₂ joins together with R₁ to form:

and, R₃ is: hydrogen; or —CH₂OCOR_(x), and R_(x) is as defined above; or a pharmaceutically acceptable salt thereof.
 43. The compound of claim 42, wherein Y is selected from the group consisting of the following compounds:


44. The compound of claim 42, wherein Z is selected from the group consisting of -hydrogen; —C₁ to C₆ alkyl optionally substituted with: —C₁ to C₆ alkoxy, -one or more halogen substituents, or -aryl; and -aryl optionally substituted with C₁ to C₆ alkoxy.
 45. The compound of claim 42, wherein Z is selected from the group consisting of -hydrogen; —C₁ to C₆ alkyl; and -aryl optionally substituted with C₁ to C₆ alkoxy.
 46. The compound of claim 42, wherein R is hydrogen.
 47. The compound of claim 42, wherein R₁ is selected from the group consisting of -hydrogen; -halogen; —C₁ to C₆ haloalkyl; -nitro; -5 or 6 membered heterocycle; —C₁ to C₆ alkoxy; -aryl optionally substituted with C₁ to C₆ alkoxy.
 48. The compound of claim 42, wherein R₂ is selected from the group consisting of -nitro; -hydrogen; -halogen; -hydroxy; —C₁ to C₆ alkyl, optionally substituted with one or more halogen substituents; C₁ to C₆ alkoxy optionally substituted with: -one or more halogen substituents, —OCOR_(x), where R_(x) is as defined above, -di-C₁ to C₆ alkyl-amino optionally substituted with C₁ to C₆ alkoxy, -5 or 6 membered heterocycle optionally substituted with C₁ to C₆ alkyl, or -5 or 6 membered heteroaryl; -amide; and —NHSO₂R_(x), where R_(x) is as defined above.
 49. The compound of claim 42, wherein R₂ is selected from the group consisting of -nitro; -hydroxy; —C₁ to C₆ alkyl, optionally substituted with one or more halogen substituents; C₁ to C₆ alkoxy optionally substituted with: -one or more halogen substituents, or -amide.
 50. The compound of claim 42, wherein R₃ is hydrogen.
 51. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 52. A pharmaceutical composition comprising the compound of claim 42 or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
 53. The pharmaceutical composition of claim 52, further comprising one or more additional anti-viral agent selected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a caspase inhibitor, an inosine monophosphate dehydrogenase inhibitor, synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a helicase inhibitor, a glycosidase inhibitor, a Toll-like receptor agonist and combinations thereof.
 54. A method for treating a viral infection in a subject in need thereof comprising administering an effective amount of the compound of claim 42 or pharmaceutically acceptable salt thereof to the subject.
 55. The method of claim 54, wherein said viral infection is a Hepatitis C viral infection.
 56. A pharmaceutical composition comprising the compound of claim 51 or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
 57. The pharmaceutical composition of claim 56, further comprising one or more additional anti-viral agent selected from the group consisting of pegylated interferon, un-pegylated interferon, ribavirin or prodrugs or derivatives thereof, a glucosidase inhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a caspase inhibitor, an inosine monophosphate dehydrogenase inhibitor, synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, a helicase inhibitor, a glycosidase inhibitor, a Toll-like receptor agonist and combinations thereof.
 58. A method for treating a viral infection in a subject in need thereof comprising administering an effective amount of the compound of claim 51 or pharmaceutically acceptable salt thereof to the subject.
 59. The method of claim 58, wherein said viral infection is a Hepatitis C viral infection. 